JP2002511850A - Allelic polygenic diagnosis and treatment of reward deficiency syndrome - Google Patents

Abstract

  (57) [Summary] The enhancement of attention processing may include an endorphinase inhibitor or an enkephalinase inhibitor, and optionally a dopamine or serotonin precursor, a GABA precursor, or an endorphin or enkephalin releaser, or Rhodiola rosea extract (Pharmaline) and And / or by administration of certain herbicidal compounds, including Huperzine. These compounds promote restoration of normal neurotransmitter function, and the combination compositions enhance dopamine release in the nucleus accumbens and are respiratory. Dopamine precursor L-phenylalanine, or L-tyrosine, enkephalinase inhibitor, D-phenylalanine, and / or serotonin precursor-hydroxytryptophan, and natural acetylcholinesterase inhibitors and chromium salts (ie, picolinate, nicotinate) Is particularly preferred, but is not limited to assisting in reducing symptoms associated with brain phenylalanine deficiency.

Description

DETAILED DESCRIPTION OF THE INVENTION             Allelic polygenic diagnosis and treatment of reward deficiency syndrome                                Background of the Invention   The U.S. Government has established the National Institute of Drug Abuse and Tobacco Related Resea According to grant number 1-R01-DA084l7 from rch Disease Program grant 4RT-0110, All rights are reserved in the present invention. 1. Field of the invention   The present invention relates, in part, to anti-respiratory compositions and to multiple neurotransmitter functions involved in rewarding behavior. The association of a number of genes with a particular genotyping. One station of the present invention The surface is how the actions of certain established neurotransmitters work together to Involvement in activating neural pathways in the body and leading to emotions of health, and Understanding the development of compositions that affect neural pathways. The present invention provides, in part, Increased memory and memory and increased concentration in healthy individuals, and increased weight loss Use of Precursor Amino Acids and Specific Herbal Compounds for Control of Strong and Bulk Eating About. Neurological disorders and behavior using genetic polymorphisms in neurotransmitter genes Various methods of diagnosis of movement, as well as those diagnosed using the compositions of the invention A method of treating a person's treatment is disclosed. Diagnostic methods for polygenic traits are also disclosed It is. 2. Description of related technology   During the past decades, research on the biological basis of drug dependence has involved rewards Some of the brain areas and neurotransmitters that could be established could be established. In particular, Dependence on alcohol, opiates, and cocaine is a common set of biochemical mechanisms (Cloninger, 1983; Blum, 1978; Blum, 1989). Limbic system And neural circuits deep in the brain, including the core nucleus accumbens and two regions called the pallidum Appear to be important in the development of rewards in humans taking drugs (Wise and And Bozarth, 1984). Chronic use of cocaine, morphine, and alcohol Has been shown to cause some biochemical adaptation in the marginal dopamine system (Ortiz et al., 1996).   The midbrain marginal dopamine system is used by the higher brain structures, especially the orbitofrontal cortex (behind the frontal front, In the anterior lobe), with the tonsils in the center of the brain, and the main part of the activity in addiction And a core nucleus accumbens that has been proven in animal studies. Multiple addictions involved The various brain pathways that occur are specific dopaminergic receptors (D1, D2, D3, D4, D5) Focus on Here, the D2 site appears to be the most prominent. Abuse of each drug, It seems to work in different parts of the circuit, the end result is the same: Dopa Min is released in the nucleus accumbens and hippocampus (Koob and Bloom, 1988). Dopamine seems to be the major neurotransmitter of reward at these enhancement sites .   Anomalies in dopamine metabolism may be associated with several behaviors (ie, iamonte, 1975), mania (Goodwin and Jamison, 1990), schizophrenia (Carlsso) n, 1978; Snyder, 1976), ADHD (Schaywitz et al., 1976), disability or aggression (Rogeness et al., 1986; Valzelli, 1981; King, 1986), alcohol abuse (Blum et al.). , 1990), and stuttering. Furthermore, DRD2 receptor The antagonist haloperidol is effective in treating some stutters (Murray et al., 1977; Prins et al., 1980). Serotonin Mechanisms of action are most frequently associated with obsessive-compulsive behavior, but dopamine Abnormalities have also been considered (Austin et al., 1991; Drlgado et al., 1990). Sight Abnormal circuits involving the floor, basal ganglia, and anterior lobe have been associated with obsessive-compulsive disorder (Ba xter et al., 1992; Rauch et al., 1994; Modell et al., 1989) and dopamine are particularly striated. And is a major neurotransmitter in the frontal lobe.   Lack of central noradrenergic mechanisms frequently leads to attention deficit hyperactivity disorder. Associated with etiology. Reading compared to ADHD children without cognitive impairment Of plasma noradrenaline (NA) in children with ADHD with and cognitive impairment Significant increases have been demonstrated (Halperin et al., Year). They have ADHD and cognitive impairment, It is proposed to be associated with NA dysregulation affecting the parietal / temporal attention center. these This is due to the co-morbid cognitive impairment, because the brain regions of Can be the cause. Occurs frequently after treatment with clonidine, from a clinical perspective At least no significant improvement in symptoms (Hunt et al., 1985; Comings et al., 1990) Associated with the role of NA in some ADHDs. Clonidine is a presynaptic a_Two Noradrenergic receptor agonists, which are involved in synaptic Causes inhibition of release to luadrenaline (Starke et al., 1974).   NA and blue spots (LC) play a role in key aspects of attention, arousal and wakefulness (Aston-Jones et al., 1984). Stress tolerance and work The above good results indicate low basal or tonic levels of catecholamines and Has been suggested to be associated with a higher acute release during mental stress ( Dienstbier, 1989). The converse is the increase in NA baseline tone during stress. Can occur in ADHD with the addition of catecholamines and reduced release of catecholamines (Pliszka Et al., 1996). To test the hypothesis that NA deficiency is involved in ADHD, NA metabolites ( 3-methoxy-4-hydroxyphenylglycol (MHPG), CSF, plasma and urine Numerous studies of ligation have been conducted. In some cases, ADHD patients control MHPG secretion (Oades, 1987; Shekim et al., 1983; Shekim, Dekirmenji an and Chapel, 1997; Yu-cum and Yu-feng, 1984), but other patients (Rapoport et al., 1978; Zametkin et al., 1985) or show no NA turnover. Show an increase (Khan and Dekirmenjian, 1981). Epinephrine level Significantly lower in ADHD subjects compared to the role (Hanna et al., 1996; Klint eberg and Magnusson, 1989; Pliszka et al., 1994) or (Girardi et al., 1995). Norepinev Phosphorus is added to epinephrine (adrenaline) by the phage encoded by the PNMT gene. It is converted by phenylethanolamine N-methyltransferase.   Based on epinephrine's inability to persistently inhibit NA neurons in locus D-amphetamine and desipyramine (both of which are A commonly used model for ADHD that leads to a significant decrease in MHPG secretion has been proposed. (Mefford and Potter, 1989; Shekim et al., 1979). However, the treatment of ADHD Methylphenidate (Ritalin), which is most commonly prescribed for And other drugs that reduce MHPG secretion (eg, Zametkin et al., 1985) For example, phenfuramine (Donnelly et al., 1989)) is effective in treating ADHD Absent. These observations suggest the presence of several types of ADHD, and multiple neurotransmitters and And gene involvement.   NA and adrenergic α2 receptor may cause posterior cortex of parietal / temporal lobe A via dysregulation in LC of strains (Posnter and Peterson, 1990; Pliszka, 1996) Playing a role in some forms of DHD, and the second form of ADHD Prefrontal attention system whose condition is associated with impulse and impairment of executive dysfunction It has been proposed that this is mainly due to the dopaminergic deficiency that affects. A few Dopaminergic genes (eg, dopamine D_TwoReceptor (DRD2)) (Comings et al. , 1991), dopamine D_FourReceptor (DRD4) (Lahoste et al., 1996), and dopami Transporter (DAT1) (Cook et al., 1995; Comings et al., 1996; Gill et al., 1997) Waldmaqn et al., 1996) have found that the gene is associated with ADHD.   Boys with and unable to read with ADHD are more likely than boys with ADHD alone Have been reported to have significantly higher plasma MHPG levels (Haperin et al., 1993; Hal perin et al., 1997). In the latter study, they also found that plasma MHPG levels and WIS Evaluated by C-R language IQ and WRAT-R (Wide-Range-Achievement Test-Revised) It showed a significant negative correlation between reading, spelling, and arithmetic problems. This difference ADHD with cognitive impairment is a different subtype of ADHD (August and Garfinke 1, 1989; McGee et al., 1989; Pennington et al., 1993). Consistent with Types of attention deficits associated with temporal lobe defects tend to be selective attention deficits It has also been suggested (Posner and Peterson, 1990; Dykman et al., 1979; Richards et al., 1990).   ADHD and cognitive impairment are associated with NA metabolism of LCs containing adrenergic α2 receptors It is suggested that it is attributable to disability and that it mainly affects the posterior attention system of the temporal lobe cortex. Has been sung (Halperin, year). These brain areas are the auditory and language processing areas Being proximal, this can cause co-morbid cognitive impairment. These are pure forms It is wrong to assume that there is. Because ADHD is a polygenic disorder (Coming s et al., 1996), and most individuals retain genes for both types. Because it seems to be transmitted. Studies in primates have shown that adrenergic α2 NAs and deficiencies in receptors also play a role in frontal lobe cognitive deficits (Arnsten, 1997).   Studies have shown that dopamine receptors are involved in addictive behavior. Have been. Cocaine patients have neuroactive levels consistent with reduced ability to receive dopamine. Show a decrease in the number of neutrons (Volkow et al., 1993). Neurons with D2 dopamine receptors Has been shown to be 25% smaller, and in morphine-addicted rats Most of their ability to receive small doses of dopamine from neurons nearby Lost (Nestler et al., 1996). D observed in opiate-dependent subjects 2 A decrease in the receptor indicates that the subject has a small amount of D2 receptor before the subject begins to abuse the drug. And that this decrease made them less susceptible to drug self-administration. It has been suggested that it may have made it more vulnerable (Wang et al., 1997).   Although the neurotransmitter system involved in reward biology is complex, at least three Other neurotransmitters are known to be involved in some parts of the brain: Serotonin in the hypothalamus, ventral tegmental area and enkev in the nucleus accumbens Alin (opioid peptide) and substantia nigra, ventral tegmental area and nucleus accumbens Inhibitory neurotransmitter GABA (Stein and Belluzzi, 1986; Blum and Koz) lowski, 1990). Interestingly, the glucose receptor is located in the hypothalamus It is an important link between serotonergic systems and opioid peptides. Another reward sutra Tract regulates the release of norepinephrine in the hippocampus from nerve fibers originating in locus Including.   Opioid and dopaminergic systems are anatomically and functionally interrelated There is evidence that these are linked to reward-related dopaminergic pathways in the brain. Opioid production in mediating the effects of ethanol and other drugs on the tract Suggest a role for utility systems. Dopaminergic dopaminergic pathway in the brain Antagonists and trauma affect preproenkephalin A activity (Morris Norman et al., 1988). Behavioral, pharmacological, and neurochemical studies Opioid agonists in enhancing the effects of abusive ethanol and other drugs And suggests involvement of dopaminergic systems (Blum et al., 1976a, b; Blum et al., 1982a Blum et al., 1977; Blum et al., 1973; Koob and Bloom, 1988, Weiss et al., 1993). Animal studies show that opiate receptor agonists are a priority for ethanol Antagonists of these receptors decrease ethanol consumption while increasing (Blum et al., 1975; Le et al., 1993). In addition, animals and chicks Studies on alcoholism in health may positively enhance the effects of alcohol consumption Suggests the efficacy of opiate receptor antagonists in reducing O'Malley, 1992; Swift et al., 1994; Blum et al., 1975; Volpi celli et al., 1992). In addition, ethanol levels of brain dopamine levels in animals Induced induction increases the opiate receptor antagonists naloxone and naxone. Ltrexone blocks both (Widowson and Hol man, 1992; Benjamin et al., 1993). Gianoukalis And a recent review by de Waele (1994) states that endogenous opioids and And support the role of drugs of abuse (ie, alcohol).   In normal humans, these neurotransmitters are responsible for the complex response between complex stimulation and complex response. Acting together in a cascade of excitations or inhibitions, this leads to a healthy, ultimately Leads to the feelings of remuneration. In the cascade theory of reward, these cell-cell interactions Destruction results in negative emotions. Genetic abnormalities (including certain polymorphisms) Stress or prolonged abuse of psychotropic drugs (including glucose) Can lead to a self-sustaining pattern of abnormal need in both animals and humans (B lum, 1991).   Pharmacological effects (bromocriptine, bupropion, and N-propylnorua) Pomorphine) is determined in part by the individual dopamine D2 genotype. DRRD2 The A1 carrier of the gene is more pharmacologically responsive to the D2 agonist. 1 One study investigated the rat core nucleus locus of N-propylnorapomomorphine, a D2 agonist. Direct microinjection into the nucleus significantly suppressed animal symptoms after opiate withdrawal, In contrast, dopamine itself has been shown to suppress alcohol withdrawal symptoms. (Harris and Aston-Jones, 1994; Blum et al., 1976b). In this regard, the brain Dopamine / endogenous opioid peptide interaction in the nucleus accumbens and elsewhere There is evidence for use. And opioid pep with endogenous opiates Overstimulation of the tide system can lead to reduced dopamine function (Pothos et al., 1991). Normal When compared to alcohol-preferred rats, alcohol-preferred rats have Lower levels of serotonin neurons in the hypothalamus Enkephalin (because it is less released) is located in the nucleus accumbens More GABA neurons and less density of D2 in certain areas of the limbic system Having the receptor (McBride et al., 1995; Smith et al., 1997; and McBride et al., 199 7).   Clinical trials are based on amino acids for certain neurotransmitters (serotonin and dopamine). Progenitors and D-phenylalanine (enkephaly by inhibiting enzymatic cleavage) Substances that promote carcinogenic activity (U.S. Pat. Nos. 4,761,429 and 5,189,064) Reduce craving when administered at the outset of either D or a carbohydrate diet; Reduces the frequency of stress, reduces the rate of recurrence, and also increases the probability of recovery Has been found to be found.   Numerous laboratories have established relationships between specific genes and various behavioral disorders (dopamine receptors). Tandem alleles and numerous impulsive compulsive behaviors). DAT₁ 1 Obtain polymorphisms linked to either the 0/10 allele or the DβH B1 allele Expression of the dopamine transporter site in Studies showing increase with SPECT scan technology (Malison et al., 1995; Tiihonen et al., 1995) Little is known other than). ADHD, Tourette's syndrome, behavior disorder, ODD, loss Reading difficulties, learning disabilities, stuttering, drug dependence, and alcoholism are all male dominants Is shown. Molecular genetic studies of DRD2, DβH, DAT (Comings et al., 1996a) and clinical Genetic studies (Comings, 1994b, 1994c, 1995b; Bierderman et al., 1991; Comings And Comings, 1987) are these pathologically related spectral disorders Indicates that Deficiencies in neurotransmitters have been suggested to be involved in alcoholism (Blum, 1991). Studies of genes involved in neurological pathways are described below.   Androgen receptor gene. Specific mutations in the AR gene It has been reported to cause Rogen insensitivity syndrome (Gottlieb et al., 1977). In addition, two sets of polymorphic trinucleotide repeats, CAG (Edwards et al.) , 1992) and GGC (Sleddens et al., 1993; Sleddens et al., 1992) ( Is present in the first exon of the AR gene You. CAG trinucleotide repeats, when extended to 43-65 times, It has been shown to cause meat atrophy (La Spada et al., 1991). Normal population The repeat length is 11-31 (Edwards et al., 1992).   Not the altitude of microsatellite and minisatellite present in the normal population Extended alleles may play a direct role in the regulation of genes. this Is based on the observation that most short tandem repeats are associated with Z-DNA formation (Schroth et al., 1992). Many times, Z-DNA has been implicated in various aspects of gene regulation. (Rich et al., 1984; Hamada et al., 1982; Wolff et al., 1996). Formed The amount of Z-DNA used is very sensitive to repeat length (Schroth et al., 1992), so that It has been suggested that the size of progeny may itself be associated with a phenotypic effect (Comi ngs, 1997).   Some but not all (Bradford and McClean, 1984; Schaal et al., 1998) (Olweus et al., 1988; Mattsson et al., 1980; Schiavi et al., 1984; Kreuz and Rose, 1972) study suggests a correlation between aggressive behavior and plasma testosterone levels . Aggressive behavior disorders are often co-morbid states in subjects with TS and ADHD (Comings, 1995; Stewart et al., 1981; Bierderman and Sprich, 1991). And there is a high degree of co-morbidity between TS and ADHD (Comings and (Cook et al., 1 995; Comings et al., 1996; Gill et al., 1997; Waldmaqn et al., 1996) Comings, 1984, 199. 0; Knell and Comings, 1993).   Dopamine D₁Receptor gene (DRD1). Control and schizophrenia, manic depression Sequencing of the DRD1 gene in patients with harm and alcoholism Exon alterations have effects on phenotypic and linkage studies in schizophrenia and TD No differences were identified (Jensen, 1991; Gelertner et al., 1993k). In the frontal cortex The D1 receptor may play a role in memory (Comings et al., 1997k; Williams Et al., 1995k). D in rats₁And D_TwoSearch for receptor agonist cocaine Antagonistic effects on behavior have been reported (Self et al., 1996). TD proband, smoker, And the pathological better found that the most consistent difference in Dde1 polymorphism was the frequency of 12 heterozygotes Relative increase in and 11 and 22 homozygotes (Comings et al., (1996)), consistent with negative heterosis. In contrast, positive Of heterozygotes are present in the DRD2 gene, with a quantitative score of 12 for heterozygotes. And highest, and 11 and 22 steps were also lowest for zygotes. DRD1 gene The results for ADHD at the locus alone were not significant, but were negative for the DRD1 gene. For the presence of heterosis and / or positive heterosis in the DRD2 gene There was a significant additive effect (Comings et al., 1997k).   Dopamine D2 receptor gene (DRD2). Previous studies have included ADHD, TS, CD, and Significantly increased prevalence of D2A1 alleles in individuals with SUD (Comings et al., 1991). Each of these disorders has a poor response to stress , And many criteria for the diagnosis of PTSD are common with ADHD The National Vietnam Veterans Readjustment S tudy (Kulka et al., 1990) found a significant correlation between PSTD and childhood symptom history in ADHD. And reported a match with the CD. Exposure to severe combat conditions in Vietnam Subjects in an addiction unit are screened for post-traumatic injury (PTSD) And the correlation of individuals with PTSD was shown to have the D2A1 allele (Comings et al., 1996k).   An association between ADHD and the TaqA1 allele of the DRD2 gene was detected (Comings et al., 1991k). Irritating methylphenidate partially increased blood flow, but not others At that time, blood flow was reduced. Changes in frontal, temporal, and cerebellar metabolism , Associated with D2 receptor density. As the density increases, the blood flow increases. Methylphenidate reduced the relative metabolic activity in the basal ganglia. these The results show that a genetic defect in dopamine metabolism results in limbic and frontal lobes. Dopaminergic state also increases the compensatory effect of dopaminergic activity in the basal ganglia. And methylphenidate mediates inhibition of dopamine transporters These through a combination that enhances brain dopamine activity in dopaminergic Inverted (Volkow et al., 1996k), resulting in a secondary decrease in dopaminergic activity in the basal ganglia Consistent with the theory that there is a decrease in hypotomic and basal ganglia blood flow. These studies also Consistent with the results of others (Castellanos et al., 1996k). In other studies, methylphen Response to nidate and its level in HVA (CSF is related to D2 receptor density Dopamine metabolite (Jonsson et al., 1996k)) shows positive correlation with CSF levels Re You. Methylphenidate has consistently led to a lack of D2 receptors in this structure. Nevertheless, it increased cerebellar metabolism (Volkow et al., 1996k; Hall et al., 1994k). this Increase the cerebellum's important role in attention, learning, and memory Consistent with emerging evidence (Leiner et al., 1989k). Between A1 genotype and partial blood flow The relationship has been reported. TaqI D2A1 carriers include putamen, nucleus accumbens, and frontal gyrus. And in the temporal gyrus and in the medial frontal cortex, occipital temporal cortex, and orbital cortex Showed significantly lower relative glucose metabolism than those with A22 genotype (Nobel et al., 1997). Taq1 D2A1 carrier is a dopamine D2 receptor in the basal ganglia ー B_max(Noble et al., 1991k). Enkephalin is It increases blood flow in areas similar to enidate, and thus includes a dopaminergic mechanism. As can be seen (Blum et al., 1985k), a significant decrease in dopamine D2 receptor density was due to detachment, Measured in individuals with social isolation and loss of close friends (Farde Et al., 1997k).   Although the DRD2 gene polymorphism has been linked to a number of mental disorders, Association with abnormal behavior (psychopathy) in affected drug users has been found No (Smith et al., 1993). Reports of an association between alcoholism and the DRD2 allele , Is very different and D_TwoAssociation found between A1 allele and multidrug / drug abuse (Smith et al., 1992, Noble et al., 1993, O'Hara et al., 1993, Comings et al., 199 4, U.S. Patent Nos. 5,210,016 and 5,500,343). DRD2 A1 and severe alcoholism After the initial association between (Blum et al., 1990), several groups I couldn't duplicate my thoughts. Two possible reasons were suggested: First, Arco Inadequate screening of drugs, drugs and tobacco abuse controls And, secondly, the characterization of alcoholism for the chronicity and severity of the disease Error (Blum et al., 1997; Bolos et al., 1990; Gelertner et al., 19) 91; Schwab et al., 1991; Turner et al., 1992; Cook et al., 1992; Goldman et al., 1992; Goldm. an et al., 1993; Suarez et al., 1994).   Dopamine serves as a regulator of many different behaviors (LeMoal and And Simon, 1991). And many studies have found that alleles of the DRD2 gene Addiction, multidrug abuse, smoking, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, visual Cognitive impairment, behavioral disorders, post-traumatic stress disorder, morbid gambling, and compulsive eating Report significant associations between them (Blum et al., 1995; Blum et al., 1996). These related Nevertheless, sequencing studies have shown that exons in exons could explain these findings No mutation was found. These findings, D_TwoA1 allele regulates DRD2 function Explain whether there is linkage disequilibrium with an unknown non-exon mutation that plays a role in (Comings et al., 1991). In addition, the severity of alcoholism and Control type is a key determinant of DRD2A1 allele association with alcoholism (Noble et al., 1994; Geijer et al., 1994; Parisian et al., 1 991; Blum et al., 1992; Blum et al., 1990; Lawford et al., 1997).   TaqI "A" RFLP and DRD in families multiply affected by alcoholism Sibling pairing performed using both microsatellite repeat polymorphisms at two loci Strand analysis reveals a link between this locus and the liability to develop severe drinking. Suggest a meaningful correlation. No corresponding mutation in the DRD2 gene has been found, This effect can arise from outside the locus of the closely linked DRD2 gene itself (Cook et al., 1996). Exon 8 of DRD2 gene in alcoholics Single point mutations have been shown (Finch et al., 1995), but others have reported that the DRD2 gene Does not report any structural mutations in the C region (Gejman et al., 1993).   DRD_TwoGene A₁Alleles include severe alcoholism, multidrug dependence, cracks / Cocaine addiction, tobacco smoking, morbid gambling, lack of major depressive episodes, and carbohydrates Numerous actions and associations, including food gluts (ie, generalized to DSM-IV drug use disorders) (Blum et al., 1996e; Blum et al., 1995b; Comings et al., 199). 6c). Compared to other Axis II diagnostic clusters (antisocial, narcissistic, delusional) The fission / avoidance cluster assessed by MCMI-II is a measure of alcohol abuse (Corbisiero et al., 1991). Advanced, showing the quality of disruption and avoidance Clusters of patients with MCMI-II tend to stay on treatment for several days And recurred early (Fals-Stewart, 1992). High scoring / evasion Raster is inpatient male alcoholism (Matano et al., 1994) and cocaine dependent Correlated with patients (Kranzler and Satel, 1994). Disruptive, including low-level sensation / Avoidance behavior consumes more alcohol than patients with high levels of sensation Expense And had a higher MAST score (Ohannessian and And Hessebrock, 1995); and avoidance personality is associated with severe eating disorders. Significantly correlated in test subjects (Yanovski et al., 1993).   Molecular heterosis in the dopamine receptor gene is Suggested in allergic diseases. HVA for dopamine, 5-- for serotonin Monoamine metabolites consisting of HIAA and MHPG for norepinephrine levels Cerebrospinal fluid levels in healthy volunteers against DRD2 TaqI AIA2 and B1B2 genotypes In the media. Results are averaged over 1,1 + 1,2 homozygotes versus 1,2. Show statistically significant differences, but with 1,1 + 1,2 vs. 2,2 genotypes and 1 allele vs. 2 alleles Not shown when analyzing for genes. TaqI B1B2 polymorphisms are virtually identical The results were given (Jonsson et al., 1996). In contrast, CSF HVA levels and DRD2 TaqI A1 / A2 polymorphisms have been tested in alcoholics in Finland and the United States, When testing one allele versus two alleles, no association is found and And 1,1 + 1,2 vs. 2,2 genotypes were not found (Goldman et al., 1992).   Heterosis in the DRD2 gene uses the TaqI polymorphism to identify the CSF of HVA with the DRD2 genotype. Indicated by level comparison (Jonsson et al., 1996k). Inattention score for TD subjects In the profile for, 12 heterozygotes score the highest attentiveness score Subjects who were 12 heterozygotes had the lowest level of CSF HVA (Jonsson Et al., 1996). The highest levels of HVA were found in 11 homozygotes and 22 homozygotes. Coalescence was moderate. Some, but not all, studies have examined ADHD and TD Children with significant lower levels of CSF HVA (Shaywitz et al., 1979k) (Cohen et al., 1979k). Significant correlation between electrophysiological abnormalities and DRD2 A1 allele (Blum et al., 1994k). These abnormalities can occur in ADHD subjects and It is found in children with alcoholism (Comings et al., 1991k; Noble et al., 1994k).   TaqA1 positive of DRD2 gene against attention deficit disorder (ADHD) and Tourette disorder Associations have been reported (Comings et al., 1991; Comings et al., 1996a), but others have reported ADH No association has been found with a proband (Sunohara et al., 1996). ADHD proband Showed a significant association with a 48 bp variant of the D4 gene, but not with DRD2, DRD3 or serotonin. No significant association with the transporter gene was shown. DRD4 confrontation seven times Remains The gene occurred significantly more frequently in the child with ADHD. D4 receptor 7-repeat alleles of genes and novelty seeking (impulsivity, searchability, Fluke, excitable, characterized by temperament and waste) There is evidence that (Epstein et al., 1996; Benjamin et al., 1996). Cocaine DRD2 A1 in extant probands was inversely correlated: low novelty exploration Gender, rigor, abstinence, fluency, avoidance, and having enhanced withdrawal control (Compton et al., 1996). Molecular genetics study alcohol With disease and substance abuse_TwoFinding an association of the dopamine receptor (DRD2) A1 allele (Blum et al., 1990). Decreased central dopaminergic function is due to the A1 allele (A1⁺ ), The subjects without (A1^-), Compared to suggested (Nobel et al., 1997). Although the causative gene of alcoholism is unknown, Many studies show a significant role for the DRD2 gene in more severe cases (Noble, 1993; Blum et al., 1995).   DRD2 gene has compulsive behavior (Comings and Comings, 1987b) and addiction, impulses It has been associated with sexual behavior, including compulsive eating, gambling, and smoking. (Self et al. Ogilvie et al., 1996; Blum et al., 1995b; Blum et al., 1996e). These activists Has previously been reported to be associated with the DRD2 gene in subjects different from the TS group. (Comings et al., 1993a; Noble et al., 1994d; Blum et al., 1996a; Comings et al., 19) 96c; Noble et al., 1994c; Noble, 1993; Comings et al., 1996e).   Dopamine D2 receptor availability is higher in alcoholic than nonalcoholic It was significantly lower. And this correlates with the number of days since last alcohol use No (Volkow et al., 1997). The ratio of DRD2 receptor to transporter availability is , Significantly higher in non-alcoholic than in alcoholic. Alcoholism D2 receptor (post-synaptic marker) Showed a significant decrease in DA transporter availability (presynaptic marker). Did not show. D2 receptors in the striatum are mainly localized in GABA cells Therefore, these results translate into the dopaminergic abnormalities seen in alcoholism. Provides evidence of a GABAergic involvement of   Dopamine D_ThreeReceptor gene (DRD3). Knockoutoma deficient in DRD3 gene Are much more active than sibling mice with the normal DRD3 gene (W illiams et al., 1995k). Negative heterosis at the DRD3 locus is associated with schizophrenia. (Crocq et al., 1992k). They found that DRD3 MscI 12 heterozygous in TD Significance in conjugation (Comings et al., 1993j) and pathological gambling (Comings et al., 1996) A significant decrease was observed.   Dopamine D_FourReceptor gene (DRD4). Dopamine D_FourReceptor gene (DRD4) A third cytoplasmic protein responsible for binding to the guanine nucleotide protein 48 bp in the DNA encoding the loop (Van Tol et al., 1992k; Lichter et al., 1993k) And 16 amino acid repeat polymorphisms have been reported. This DNA region is repeated 2 to 11 times The most common alleles are 2, 4, and 7 repeats. 7 pairs Progenitor responds slowly to dopamine with respect to intracellular adenyl cyclase inhibition (Asghari et al., 1995k). Two independent studies of normal subjects showed seven alleles Presence and novel search (this is a trait associated with impulses (Benjamin et al., 1996k; E bstein et al., 1996k)). One study is concerned with such a relationship. No run was found (Malhotra et al., 1996). ADHD children compared to controls Studies show that more children with ADHD have at least one (LaHoste et al., 1996k). 7 conflicts of DRD4 in TD An association with the gene has been reported (Grice et al., 1996k). Other research in this area The consequences are not ambiguous (Spielman et al., 1993k).   Dopamine transporter gene (DAT1). At the vesicle transporter locus Of DAT1 gene markers in different Caucasians (white) from different European countries Color) showed substantial negative homogeneity in Americans, but no clear link to drug abuse It was not clear (Uhl et al., 1993; Persico et al., 1993). DAT1 VNTR allele Distribution is control sample for any drug user or stimulant abuser (Persico et al., 1996), but an association with Japanese alcoholism was observed. (Muramatsu and Higuchi, 1995). The DAT1 gene also affects obsessive-compulsive disorder and And have a role in addiction disorders. Of the action of cocaine Since one of the modes is to inhibit dopamine transporter function (Ritz et al. Ritz et al., 1990), implicated in drug addiction biology and Ki Others, including Nsonson's disease (Uhl et al., 1990) and Tourette's syndrome (Singer et al., 1991) Disability has also been implicated.   Increased dopamine transporter site in Tourette syndrome Have been demonstrated using the Yang technology (Malison et al., 1995), and dopamine trans The porter receptor site is used for violent alcohol compared to non-violent alcoholism. Was significantly increased in the disease (Tiihonen et al., 1995). Postmortem sample of TS subject Have reported an increase in the number of dopamine uptake sites in the striatum. this is Suggests either an increase in the number of DAT1 molecules or an increase in the number of dopamine nerve endings (Singer et al., 1991). This includes methylphenidate (Volkow et al., 1995k) and Is the site of action of dexedrine, a compound widely used in the treatment of ADHD . These stimulants inhibit the transport process, which leads to increased synaptic dopamine. Bring. Dopamine transporters in TD subjects versus control striatum Significant increases in protein levels have been reported (Maison et al., 1995k). DAT1 Knockout mice, which are very hyperactive in confined spaces Studies show a 5-fold increase in brain dopamine levels, D_TwoReceptor down-regulation Ration, D_TwoShows 57% reduction in body size and uncoupling of receptor function (Giros et al., 1996k). Less common DAT1 repeat allele is the number of DAT1 molecules It is not known whether it is associated with an increase or decrease.   Correlation between the 10 alleles of the DAT1 gene has been reported in ADHD / ADD cases (Cook et al., 1995k), and behavioral changes were reported in Tourette's disorder (TD). (Comings et al., 1996). A significant increase in subjects with autism was T S and autism are genetically related and show a similar set of genes Consistent with suggested studies (Burd et al., 1987; Comings and Comings, 1991b; Sverd, 1991).   Prevalence of 9 repeat allele VNTR polymorphisms in the 3 'untranslated region of the DAT gene Significantly increased compared to 93 ethnically matched non-alcoholic controls In 93 alcoholics exhibiting withdrawal seizures or delirium (Sander Et al., 1997). 5 'UTR 40 bp repeat polymorphism in DAT1 indicates that subjects with drug abuse And any 3'UTR repeat pair compared to normal controls No significant difference was found in the frequency of progeny. (Persico et al., 199 3). 9/10 genotype has been shown to be associated with "pathologically violent" adolescents; The 9/9 genotype is associated with alcohol dependence with withdrawal seizures or delirium. Coca Reported relationship between 9 alleles of 40 bp repeat of DAT1 gene with in-induced delusion (Gelernter et al., 1994a).   Dopamine-β-hydroxylase. DβH is a key enzyme for dopamine metabolism One, and catalyzes the conversion of dopamine to norepinephrine (NE). Every time In experimental animals, inhibition of DβH activity results in reduced norepinephrine levels It releases inhibitors of tyrosine hydroxylase and overproduces dopamine. Bring. The latter is associated with hyperactivity, aggression, self-stimulation, and stereotypy ( Randrup and Scheel-Kruger, 1966; Shekin et al., 1983k). DβH blood enzyme level Leu's work has been described in the search for excitement (Kuperman et al., 1988k; Comings et al., 1996), ADHD and Role of this enzyme in dysfunction (Rogerness et al., 1982k; Rogerness et al., 1989k) Associated.   The barrier to dopamine β-hydroxylase (DβH) activity has previously been It has been associated with Lucor's disease (Pliszka et al., 1991). Extraversion disorder (eg C D) decreases in noradrenergic function and in dopaminergic function Increase, which may be associated with some of the symptoms (Quay, 1986). Others find that emotions with low plasma DBD levels are impaired Reported increased frequency of CD diagnosis in affected boys. But Bowden et al. , 1988, an outpatient study showed that low DβH levels in children with ADHD also had CD Find that it seems to be more present than ADHD children without CD (Rogeness et al., 1987; Pliszka et al., 1988; Bowden et al., 1988; Comings et al., 19) 96). In contrast, in outpatient studies at juvenile training centers, CD and plasma D No association with βH was found. Umberkomen et al. (1981) reported a low DβH level. It showed a correlation between the behavior and the excitement seeking behavior.   Have a variety of mental disorders, including major depression, bipolar affective disorder, and schizophrenia Testing for CSF DβH levels in patients with low CSF DβH and bipolar affective disorder Only significant correlations were found (Lerner et al., 1978). DβH locus and schizophrenia (As chauer and Meszaros, 1994), alcoholism, depression, manic depression, and Tourette's disease Linkage studies between the affected group (Comings et al., 1986) were negative. But some A sibling-pair analysis of ABO blood types and DβH, some mental disorders (eg, depression, al (Wilson et al., 1992).   DβH locus and schizophrenia, alcoholism, depression, manic depression, and Tourette's syndrome Linkage studies between groups were negative (Aschauer and Meszaros et al., 1994; Comi ns et al., 1986). No association found between D.BETA.HTaq1B1 allele and pathogenic SAB (Blum et al., 1997). Taq1 B1 / B2 polymorphisms include drug, alcohol, and Correlate with controls screened to rule out tobacco abuse Was reported. However, the B1 allele of the dopamine β-hydroxylase gene does not. It has also been associated with TD probands and ADHD probands (Comings et al. (1996)).   Cannabinoid receptor (CB1). Cannabinoid receptors and reward pathways May be primary, but perhaps this effect has an effect on dopamine metabolism. It appears to be secondary through the regulatory effects of soy and cannabinoid receptors. You. This is due to the similarity between the results at the CB1 and DRD2 receptors. Matches. Genetically modified DRD2 gene with multiple drug abuse, similar to CB1 gene Is more reproducible than that of alcoholism itself (O'Ha ra et al., 1993; Smith et al., 1992; Noble et al. 1993; Comings et al., 1994). These original Our interpretation is that the dopaminergic cannabinoid reward pathway is More activated by drugs, especially cocaine and amphetamine (DiChiara and Imperato, 1988).   Activating systems of the mesolimbic dopamine system are used to detect cocaine in drug-dependent animal models. It is known to induce recurrent behavior. This triggering effect is dopamine D_TwoJaw Dopamine D₁Inhibited by agonists (Se lf et al., 1996). In this regard, in the striatum, D₁And D_TwoOf the receptor ratio The ability of anandamide to cause a decrease (Romero et al., 1995) is It may be a linkage that explains the role of the CB1 variant.   Monoamine oxidase. Fn associated with the T → C variant at position 1460 of MAO-A cDNA The u4H1 polymorphism and the EcoRV polymorphism associated with the T → G variant at position 941 were tested (Hotamisligil and Breakfield, 1994). Both are replaced by the third base of the codon These are not related to amino acid substitutions. These are known Forty cell lines with MAO-A activity were tested. All strains with the Fnu4H1 C variant are also And ExoRV G variants. Two groups of samples based on low MAO-A activity versus high MAO-A activity Are divided into the less common Fnu4H1 C or + alleles (the present inventors Their two alleles, which were present in 25% of the cell lines, were significantly different from the highly active group. (P = 0.028). Lin et al. (1994) describe the more general MAOA Fnu4 H1 T or one allele (these are associated with low MAO levels in manic depression (Lin Et al., 1994)) (Lin et al., 1994) radd  Vanyukov et al. (1993) reported MAOA remains in 23 male and 34 female alcoholics. Genes were compared to 31 male and 78 female controls using the CA repeat polymorphism (Black et al., 1991). High molecular weight alleles in young drug abusers ( > 115 bp), there was a trend (P = 0.17) in men, (P = 0.8) is absent, and there is a slight association of> 115 bp allele with age of onset. (P = 0.03). (1996) recently showed a> 100-fold change in MAO A enzyme activity. The exons of the 40 control males that showed motion were sequenced. Coding sequence prominence There was no preservation. Only five polymorphisms were found. Of these, Four contained a third codon position with no change in the amino acid sequence. The other is neutral Ly It was s → arg substitution.   Nicotine receptor gene. The gene for the CHRNA4 gene is chromosome 20ql3. 2-13.3 (Steinlein et al., 1994) and spanning 17 kb of genomic DNA Consists of exons (Steinlein et al., 1996). In transmembrane domain 2 of CHRNA4 gene Ser248Phe missense mutations in one long Australian kindred have autosomal dominance Has been found to be associated with nocturnal nocturnal frontal epilepsy (ADNFLE) (Steinlein et al., 1). 995). 3 nucleotides into the coding region for the C-terminal end of the M2 domain Insertion (GCT) was performed in a Norwegian family with autosomal dominant nocturnal frontal lobe epilepsy (Steinlein et al., 1997b). Brain function, benign familial neonatal convulsions (Lepper t et al., 1989; Malafosse et al., 1992) and low potential EEG (Steinlein et al., 1992). Other disorders have also been linked to regions of the CHRNA4 locus. D20S19 (this is Loci that are highly polymorphic) have these residuals for all three disorders. It is closely linked to the gene (Steinlein et al., 1996).   Highly polymorphic dinucleotide VN located in the first intron of the CHRNA4 gene TR polymorphisms have been reported by Weiland and Steinlein (Weiland and Steinlein lein, 1996). Single base pair polymorphisms have also been reported (Steinlein et al., 1995). Phillips and Mulley, 1997; Guipponi et al., 1997; Steinlein et al., 1997a). 3 Steinlein et al. (1997a) found that using a single base pair polymorphism No association was found with panic disorder. ADNFLE and four silent polymorphisms Using the relevant Ser248Phe missense mutation (Steinlein et al.), Mutations are common idiopathic generalized epilepsy in childhood (0.085) versus control (0.027) Reported a modest increase in the frequency of the T allele of the Cfo1595 polymorphism in.   Micro / mini satellite polymorphism. In different neuropsychiatric candidate genes Studies of behavioral phenotypes associated with micro / mini-satellite polymorphisms have shown various quantitative Shorter or longer alleles with different behavioral traits and We found a significant association between nisatellites or microsatellites: MAOA , MAOB, HTR1A, DAT1, DRD4, HRAS, HTT, OB, CN1, LGABRA3, GABRB3, FRAXA And NO (Comings et al., 1996k; Comings et al., 1996l; Comings et al., 1996m; Johnso n et al., 1997; Comings et al., 1998; Gade et al., 1997). Identical polymorphisms in the following genes Significant phenotypic behavioral effects of specific size alleles: DAT1 (Cook et al., 1995; Gele rnter et al., 1994) DRD4 (Benjamin et al., 1996; Ebstein et al., 1996; Grice et al., 1996; L. ahos T (Ogilvie et al., 1996; Lesch et al., 1996), INS (Bennett et al., 1955; Kennedy et al., 1995) Pugliese et al., 1997; Vafiadis et al., 1997) and DBH (Wei et al., 1997). these Studies have shown the importance of single base pair changes in a subset of these length variants. Does not rule out the existence of roles (below and Grice et al., 1996; Lichter et al., 1993; Kronti ris et al., 1985).   Evidence exists for the involvement of long triplet repeats in various neuropathies (Caskey et al., 1992). This is because of Fragile X Syndrome, Huntington's Disease Disease Collaborative Research Group, 1993), dystrophic, Kennedy disease, Including Rietraich's ataxia (Campuzano et al., 1996) and others (Caskey et al., 1992) No. At least five of these disorders are identified in the amino acid sequence of each gene product. Contains intronic GAG repeats that result in polyglutamine adducts.   Obesity-related genes. Previous studies have shown that human OB genes in hundreds of obese individuals Did not identify any mutations (EzzeLl, 1995; Hamilton et al., 1995). Considine et al., 1996b). However, previous studies (Comings, 1996b; Comings et al., 1) 996c) that the mutations involved in the polygenic disorder can be outside the exons, and Polymorphic dinucleotide repeats themselves play a role in regulating the expression of genes close to them (Krontiris et al., 1993; Green and Krontiris, 1993). Trepicchio and Krontiris. 1992; Trcpicchio and Krontiris, 1993; Benn ett et al., 1955; Kennedy et al., 1995).   The TaqI polymorphism in the apolipoprotein gene (APOE-D) has been associated with obese subjects. And a link between APO-D and starved insulin was found. This study shows that APO-D polymorphisms have gene markers for both obesity and hyperinsulinemia. Suggests that it may be a car (Vijayaraghavan et al., 1994).   Serotonin gene. Functional variants of this gene have been Increase or decrease the observed irritancy of both nin and tryptophan I can explain. Four different polymorphisms of the human TDO2 gene have been identified. Related Lab Studies have shown significant differences between one or more of these polymorphisms and TS, ADHD, and drug dependence. The correlation is shown. Intron 6G-T variant is significantly associated with platelet serotonin levels (Comings et al., 1996a).   Multigene analysis. Dopamine D4 receptor gene (DRD4), cannabinoid receptor Combination test of the target gene (CNR1) and GABAB3 receptor gene (GABAB3) Explained 25% of the variability in traits of IV drug use (Saucier et al., 1996; Comings et al., 19). 97; Johnson et al., 1997). Testing for both OB and DRD2 genes Explain that it was observed to show 22.8% of the variation of the weight index. This is polygenic Child factors affect weight, but may be associated with psychiatric symptoms as determined by the study alone. The association demonstrated that it accounts for a small proportion (Comings et al., 1996b). Three dopa Mi Polymorphisms in the dopaminergic genes: TaqIA1, dopamine D2 receptor (DRD2), TaqIB1 of pamine β-hydroxylase (DβH) and dopamine transporter ( DAT1) The 10/10 genotype of the 40 bp repeat of the gene has significant association with TS, ADHD, and CD (Comings, 1996).   Role of neurotransmitters and amino acid precursors. May be involved in neuropathy In addition to genes, neurotransmitters and drugs create certain psychological traits, Or their role in mitigation is being studied. In humans, medium Dopaminergic activity of the meso-prefrontal is involved in human cognition It has been suggested (Weinberger et al., 1988). Patients with Parkinson's disease and And possibly schizophrenia (activation of the prefrontal cortex during cognitive work, and clinical In patients (with signs of dopaminergic function) (Weinberger et al., 1988k). animal Chemical turnover of the brain in rats is due to precursor amino acid loading, or systemic and direct Demonstrated changes in neurotransmitter levels following indirect central nervous system delivery (Blum Et al., 1996a; Blum et al., 1996b). Animal studies are based on search activity and search (ex) ploratory) activity, distractibility, response speed, discriminatory ability and attention NE and dopamine in a wide range of attention-related actions involved in switching Related. Overall, animal and human studies have been conducted early and late in information processing. Indicate the role for dopamine and NE in each (Sara et al., 1994k). Go Some neurotransmitters (particularly dopamine, serotonin, norepinephrine, GABA, Glutamine and opioid peptides (which regulate brain function and mood (mood regulation) plays an important role in their precursor amino acid nutrition Can be dramatically affected by circulating levels (Wurtman, 1981k). Data is for amino acids Precursor and Enkephalinase Inhibitors Cause Alcoholism, Cocaine Have a substantial effect on poisoning and recovery from food addictions. Suggest to provide. (Blum et al., 1987a; Blum et al., 1987b; Blum et al., 1987c; Blum Et al., 1989b; Blum et al., 1990; (Strandburg et al., 1996).   One important function of catecholamine innervation in the cerebral cortex is the control of attention. Can get. Injection of catecholamines from the reticulum into the cerebral cortex, ie ventral of the midbrain Dopamine neurons in the tegmentum (ventral tegmentum) and the upper pons (upp Of particular interest are the neuritic NE neurons in er pons). Acetylcholine action Both cognitive (ACH) and dopaminergic (DA) systems provide accurate cognitive performance ) Has been found to be important for maintenance. Radial-arm stray A series of studies examining these aspects of cognitive function revealed by roads We have found these two neurotransmitter systems interacting in a crude manner (Levin et al., 1995). Deficiencies in choice accuracy are due to the muscarinic ACH receptor. Or induced by blocking either the nicotinic ACH receptor . Selection induced by blocking muscarinic receptors using scopolamine Deficiencies in accuracy were reversed by the dopamine receptor blocker haloperidol Get reversed. The specific DAD1 blocker SCH23390 also has this effect , Whereas the specific D_TwoThe blocker raclopride has this effect. Had no fruit. D_TwoThis was seen with the antagonist raclopride The effect is D₁Not found for the antagonist SCH23390. D_TwoThe receptor is Of the selective D2 agonist LY1771555 caused by mecamylamine Findings suggest that nicotinic effects on cognitive function are reversed Was. The effectiveness of these selective DA treatments in reversing cognitive deficits , Due to insufficient under-activation of ACH (Levin et al., 1990k).   There is accumulating evidence that serotonin is present in several areas of the mammalian brain. Being able to modulate cholinergic functions and their serotonergic properties Suggests that cholinergic interactions affect cognition. Serotoni Memory disruptions induced by the simultaneous manipulation of the nergic and cholinergic systems, Conclusion not necessarily due to serotonergic modification of cholinergic system It is attached. The cognitive ability of an organism is, for example, the ability of brain structures such as the hippocampus or cortex to Arising from interactions between several neurotransmitters like DA in Classic memory functions (eg, attention, alertness, sensory accuracy, etc.) To memory of other systemic functions that may involve a different cerebral matrix than the related cerebral matrix It also results from effects (Cassel et al., 1995k).   In addition, exogenous alterations in the hippocampal theta wave (hippocampal theta) For simultaneous activation of medial septal input and medial septal input It has been determined to be dependent. Cholinergic injection produces a hippocampal θ wave. Afferent excitat on the hippocampal theta-on cell ory drive), and the GABAergic ejection of the septum is a GABAergic mediator in the hippocampus. Ron (hippocampal theta-off cell) that does not emit θ waves Act to reduce the overall level of inhibition. In both activities, Must be present for generation of hippocampal theta wave region and cellular activity. Colin The balance between the utility and GABAergic systems is either hippocampal synchronous (theta wave) or asynchronous. Can be determined (Smythe et al., 1992).   Other neurotransmitters such as norepinephrine (NE) also play a role in learning and memory. And can play a role. The neuromodulatory properties of NE are characterized by coeruleocortical (L C) NE injection should play an important role in the process of attention and memory Suggest that. For example, gating of NE released in the target sensory system (ga The ting and tuning actions are stimuli associated with crisis times of change. (Sara et al., 1994). Other surveys show that during stress periods The result of one LC activity or physiological challenger is that DA and NE Through both releases, suggests that arousal may be increased or maintained (P age et al., 1994).   NELC neuron discharge in behavioral rats and monkeys It has been reported to suggest a role for the LC system in the regulation of mental state or sensation (Aston-Jones et al., 1991k). Further investigation in the study of NE in the dentate gyrus Promotes both short- and long-term responses to complex sensory inputs Support a role for LC in the context of LC and in memory and attentional processing (Harley, 1988k). Exogenously applied or intrinsic NE released in a timely manner is associated with short-potentiation and long-term potentiation (L TP).   A subkinetic neurokinin for memory, reinforcement and brain metabolism Effects of Stance P (SP) and its N-terminal and C-terminal fragments Research dealing with. When applied peripherally, Sp can promote and enhance memory. Was shown. But most importantly, these effects differ due to the different SP sequences. It is a finding that it seems to be coded. Because N-terminal SP1-7 increases memory Whereas the C-heptapeptide and hexapeptide sequences of SP This is because it was found to be enhanced by an equimolar dose. These differential behavioral effects The result is DA activity (as both SP and C-terminal (but not its N-terminal) activity) DA in the nucleus accumbens (Nac) in response to selective and site-specific changes in Increase, but not neo-striatum. These results are That the enhanced action of the SP administered topically can be mediated by its C-terminal sequence; And show that this effect could be related to DA activity in NAC (Huston et al., 1991k).   Regarding dopaminergic activity, previous studies have shown that D_TwoDopamine receptor agonis Bromocriptine is present in vaccinated human subjects Have a beneficial effect on the memory function of interworking (Kimberg et al., 1997). This memory where several aspects of the stimulus are maintained over short time intervals Formation of lesions and single unit recordings using monkeys Prefrontal cortical function in both learning and neuroimaging studies in humans (Goldman et al., 1987k; Jonidas et al., 199 3). Dopamine D reduces release rate in alcoholism_TwoReceptor remains A selective positive effect of bromocripurine as a function of transmission has also been reported. (Lawford et al., 1995). In addition, the delay in monkeys performing memory tasks Of dopamine antagonists directly on neuronal activity in the priod The effect has been demonstrated (Williams et al., 1995k). Is a dopamine releaser Phentermine is involved in weight loss (Weintramb et al., 1992) .   In addition, the pharmaceutical manipulation of brain dopamine concentration has been used in humans and animals Affects memory, the latter affecting localization to prefrontal cortex. But, The effects of dopamine agonists on humans are still poorly understood. B Lomocriptine is a cortical dopamine receptor in the area that emanates against the neocortex And prefrontal cortex via its effect on neuronal and sub-cortical receptors It has been hypothesized that it has effects on quality-related cognitive functions (Kimberg et al. 1997). They may block young normal subjects depending on their working memory ability. We found the effect of mocriptine. Subjects with higher performance are more likely to respond to the drug In subjects who perform poorly and have a low capacity for this, Improved. These results indicate that dopamine-mediated working memory in humans We demonstrated an empirical association with high-level cognitive function. The DRD2 A1 allele is also Have been shown to be associated with defects in visuospatial memory (Bernan et al., 1995k).   A double-blind study was conducted in alcoholic carriers (A1 alleles (A1 / A1 Type A and A1 / A2 genotype), or A2 allele (A2 / A2) only)_Two Administration of the agonist bromocriptine or placebo is Reduced craving and anxiety between A1-treated carriers Prove that. Attrition rates are based on placebo-treated A1 carriers Was the highest. The effect of bromocriptine on A1 carriers is 6 weeks Was much stronger when applied for a period of time. Dopamine D_TwoJaw Nist, bromocriptine, could improve higher levels of cognitive function.   Studies using sophisticated techniques in animals (including microdialysis measurements) ) Demonstrated changes in neurotransmitter output following precursor amino acid loading (Her nandez et al., 1988). In addition, in animals, the change in behavior is caused by the precursor amino acid, Proven following systemic and direct central nervous system delivery (Blum et al., 197 2). Certain L-amino acids are neurotransmitters and precursors of neurotransmitters Thus, their racemic D-amino acids also have biological activity. Special In addition, D-phenylalanine, D-leucine, other amino acids and certain metabolites (e.g., For example, hydrocinnamic acid) is used to regulate mood and behavior. Decreases the degradation of central opioid peptides (Blum et al., 1977; Della Bella 1980).   In some individuals, scientists have described phenylalanine deficiency (PHD) (Lou, 1994k). In this regard, phenylalanine and tyrosine are In turn, the first two steps in the biosynthesis of dopamine, a metabolic precursor of NE, Constitute. Extracellular phenylalanine levels increase in PHD due to reduced dopamine synthesis Affect brain function. Induction of slowing of EEG has been shown and The performance time in the psychopsychological test was extended. Fir in the CNS Concentration is reduced in PHD, possibly due to competitive inhibition (eg, blood-brain barrier). Insufficient tyrosine substrate for catecholamine synthesis due to Means that. In experimental studies, dopamine synthesis and release was Have been shown to be affected by increased availability of services. In PHD 3 extra doses of tyrosine (160 mg / kg / 24 hours) ke) reduces reaction time, reduces variability, and is In a crossover study, a similar dose was modified in a psychological study. It has been reported to induce good whereas low doses do not.   The combination of precursor amino acids having enkephalinase inhibitory activity is (US Pat. No. 5,189,064). Cocaine Steep Sexual use may improve certain aspects of brain electrophysiological dysfunction (Maurer Et al., 1988k). Chronic cocaine abuse alters attention processing (Noldy et al., 1990 k). Acute cocaine use improves certain aspects of brain electrophysiological dysfunction It is known that this can be done (Jonsson et al., 1996). But paradoxically, chronic Cocaine abuse alters attention processing (Braverman and Blum, 1996). What Note that, although controversial, attentional processing depends on the regulation of biogenic amines. (Lyoo et al., 1996).   Obesity and neurological function. Obesity is generally more than 20% of ideal body weight Defined. Numerous methods of weight loss have been attempted, including low calorie beverages. Lance diet, "fad" diet, behavior-improving drug (ie, D- Fenflower amine (D-phenflouramine), phenteramine Etc.), surgery, total starvation, jaw wiring , And combinations of these methods. Most of these are Is a short-term approach to the Can cause even more serious risks (Lockwood and Amatruda, 1984). Was Even if short-term weight loss is indicated, the weight is usually Recover after interruption of jime. Also about the fact that about 28% of the United States population is obese Regardless, obesity is a cosmetic rather than a broad health indicator. Recognized as food-addiction, a self-imposed condition with an indicator (Kral et al., 1989; Weintraub and Bray, 1989).   An understanding is that some recent studies of the causes of obesity and the treatment of this condition Difficulty comes to the fore. Twins in Pima Indians Studies have demonstrated a strong genetic basis for obesity (Bouchard, 1989; St. unkard et al., 1990). Obesity is a heterogeneous (both genetic and environmental) component. It is a heterogeneous and prevalent disorder. Macroscopic selection of various foods The relationship between choice and familial drug use disorder (SUD) is related to alcohol, nicotine, And dopaminergic potentiation by carbohydrates (tybel) has been demonstrated through literature and neurochemical studies (Nobel, 1 998; DiChiara, 1988). In this regard, both obesity and SUD have It can be considered that there is. Dopamine D2 receptor (DRD2), and dopamine transporter Some genes, such as the promoter (DAT1) gene, are risk factors for obesity. Not only (Noble et al., 1994; Comings et al., 1993; Blum et al., 1995a) It may also be a risk factor for UD and other psychiatric disorders (Noble et al., 1994; S mith et al., 1992; Comings, 1994; Bium et al., 1995b; Comings et al., 1996; Cook et al., 1995). Furthermore, the cloning and sequence of the mouse ob gene and its human OB homolog Determining that a defect in this gene plays a key role in causing obesity in humans And its gene product, Leptin, And usefulness (Zhang et al., 1994; Peileymounter et al., 1995). Genetic effects can work alone, but in most cases, Is the only genetic-environmental interaction (that is, the body that is associated with increased food). Set a stage to define opportunities for dramatic increases in weight. Such a genetic For those with a very dangerous profile, obesity is no less than any other chronic illness. It is a life-long condition requiring long-term treatment.   Uncontrolled intake of alcohol, drugs, and food, especially carbohydrates The specific causes of behavior are not completely understood. Nevertheless, these Forced appetite behavior is a genetic predisposition and environmental insult fact. ors) factor. Numerous studies of opiates, opio Id peptide, CCK-8, glycogen, DA, and insulin (using glucose ) And selective carbohydrate intake (Morley and And Levine, 1988; Moore et al., 1982; Morley et al., 1985; Riviere and Bueno, 1987). The primary neurotransmitters involved in feeding behavior include monoamines (dopami (DA), norepinephrine (Ne), epinephrine (EPI), and serotonin (5-HT) Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter; and pancreatic polypeptide , Opioid peptides, hormone-releasing factors, and various gut-brain Various neuropeptides such as peptides (for review, see Coopc r et al., 1988; Gosnell, 1987; Bouchard, 1994). One in the midbrain margin reward system Brain monoamines and neuropep in control of normal eating behavior Extensive evidence exists for many roles of tides (Leibowitz and Hor, 1982) . Cerebrospinal fluid analysis in both humans and animals is associated with abnormal eating patterns Show specific disturbances in the neurochemical function of the developing brain (Kaye et al., 19 85; Kaye et al., 1984).   The study of overeating is based on various PHENCAL^TM(This is a diet containing amino acid precursors. Study subjects who take dietary supplements) On average, a 27 pound reduction versus a 10 pound reduction in the control group. (Blum, 1990). Alcoholics, multidrug abusers, heroin abusers, and PHENCAL when using cocaine-dependent individuals^TMOr other similar neuronutrition ( Blum et al., 1988c; Blum and Trachtenberg, 1988; Cold, 1996) facilitated the recovery. To provide a common mode of treatment for addiction to these diverse substances. (Blum et al., 1996; Blum et al., 1997).   The role of nicotine   Nicotine also releases dopamine, and nicotine is used in rats, monkeys, and rats. And various tests in humans have been found to improve memory performance (DiChiara et al., 1988). Nicotine is a discriminatory behavior in rats in a dose-dependent manner Reduced inaccurate response to (Geller et al., 1970). This effect is Similar to chlordiazepoxide, but mimicked by irritating caffeine Could not be imitated (Geller et al., 1970). Gum or skin patch form (Sanber g et al., 1988; McConville et al., 1992; Sanberg et al., 1997); urette) in treatment of tic in some subjects with syndrome (TS) Effective, and cigarette smoking is important for attention, alertness, learning and learning. And strengthening memory (Wesnes and Warburton, 1984; Warburton, 1992; B 1996; Conners et al., 1996; Levin et al., 1996).   To determine the effect of using nicotine in the treatment of adults with ADHD, A placebo-controlled, double-blind study has been reported (Levime et al., 1996; Conners Et al., 1996). Six of the 17 subjects were smokers and 11 were non-smokers. all All humans meet the diagnostic criteria of DSM-IV for adult ADHD. Drugs to non-smokers Via a transdermal patch at a dosage of 7 mg / day, and 21 mg / day for smokers. Delivered. Apply active and placebo patches approximately one week apart. In a counter-balanced order. Nicotine, Clinical  It caused a significant overall improvement in the Global Impressions (CGI) scale. This effect is significant, even when considered only in non-smokers, and Withdrawal symptoms from smoking were not due to relief. Nicotine Significantly increased as measured by the Profile of Mood States (POMS) test. Force (vigor) and overall reaction time in Continuous Performance Test Caused a significant decrease. There was also a significant decrease in the inattentive index. D Cochin improves the accuracy of time estimation, and Reduced line variability. Smoking is more common in adults with ADHD than in adults without ADHD (Conners et al., 1996).   Interaction between nicotine and dopamine systems may be important for this effect. A series of interactions of nicotinic agonists and antagonists with the dopamine system In this study, rats used a win-shift in a radial arm maze. Performed in working memory tasks (Levin and Rose, 1995k). Nicotine antago Working memory defects caused by the meristylamine mecamylamine were identified as D1 / D2 DA The antagonist haloperidol and the specific D2 antagonist lac Enhanced by loprid. In contrast, the mecamylamine-induced defect was D2 / D3 It was reversed by co-administration of the agonist quinpirole. Nicotine also Significant interaction with dopamine drugs on working memory performance in radial arm maze Having Pergolide, an agonist of dopamine, in its own right Did not improve the selection accuracy of the shape. Nicotine is effective in reversing this defect Met. When given together with nicotine, the D2 / D3 agonist quinpiro Have improved RAM selection accuracy compared to either drug alone. midbrain Topical injection of mecamylamine into the dopamine nuclei of the rat Effectively impairs the working memory function in the radiating arm (Noble et al., 1998).   The role of chromium salts (CrP and CrN). Trivalent chromium helps normal insulin function It is an essential mineral (Jeejeehboy et al., 1977; Schwartz et al., 1959). Not all Some previous studies have shown that chromium supplementation, coronary artery disease (CAD), and Demonstrates that risk factors for phosphorus-independent diabetes (NIDDM) can be advantageously altered (Abraham et al., 1992; Anderson et al., 1991; Donaldson et al., 1985; Glinsmann 1966; Kaats et al., 1991; Levine et al., 1968; Page et al., 1991; Press et al., 1990; Roeback Et al., 1991). Chromium changes these via its potentiating effect on insulin (Offenbacher et al., 1988).   Animal studies indicate that CrP can reduce insulin resistance and that body composition (co malign) (Liarn et al., 1993). Finds Positive Changes in Body Composition Using CrP Supplement (Hasten et al., 1992), another is a statistically significant change in body composition But not positive (Hallmark et al., 1993), and thirdly Did not find any positive changes in body composition with CrP supplementation (Cl ancey et al., 1994). CrP supplementation can reduce body composition, especially the reduction of excess body fat (Page Et al., 1992). However, simultaneous chrome complement Earlier studies observing exercise and exercise training showed that Conflicting results are used to limit effects on body weight and composition (Clancy Evans et al., 1989: Evans et al., 1993; Hallmark et al., 1996; Hasten et al., 1992).   In general, chromium salts (picolinate and And nicotinate) still exist (Abraham et al., 1992; Anderso n, 1995; Hallmark et al., 1993; Clancy et al., 1994; Bulbulian et al., 1996), but some The report seems to support positive changes in the composition of the human body. (Kaats et al., 1996). In contrast, (Grant et al., 1997; Bulbulian et al., 1996) Of weight gain using chromium picolinate in humans with and without bleeding However, in the same population, a positive effect on nicotinate (Kaats et al., 1992).   Chromium picolinate (CrP) has been most extensively used, studied, and Promoted compounds, but in vitro studies have shown that chromium nicotinate May also be practical in areas of weight loss and changes in body composition. Previous studies have shown that chromium picolinate supplementation reduced fat mass and To increase fat-free mass (Kaats 1991; Page et al., 1991). Earlier studies of exercise training also included fat It shows no mass gain (Stefanick et al., 1993). Young men (Evans, 1989) and In a study using humans and women (Hasten et al., 1992), exercise training and chromium picolinate Changes in body composition when exercise training is combined with supplementation But this finding has not been confirmed (Clancy et al., 1994; Hallmark et al., 1996). Nicotinate (CrN) is even more important than picolinate Has been reported (Grant et al., 1997).   Nutritional supplements in the treatment of behavioral disorders. Disruption of neurotransmitter action is Can Underlie Medical and Behavioral Injuries (Blum et al., 1996c; Persico and Uh l, 1997; Noble et al., 1991). In particular, dopamine, serotonin, norepinephrine, γ Anomalous aminoamino acid (GABA), glutamine, and opioid peptides Modulation may be associated with poisoning disorders, especially those involving alcohol and cocaine abuse. And play an important role (Pohjalainen et al., 1996). as a result, These observations indicate that the intake of selected nutrients affects mood and thus human behavior. It gave momentum to the idea that it could. Nutritional strategies are overkill (Grandy et al., 1989), but the proof of effect is clearly limited. Have been. Recovery from certain RDS behaviors, including alcohol, cocaine, and overeating Of the combination of amino acid precursors and enkephalin inhibitors against Effects have been demonstrated (Noble et al., 1993; Noble et al., 1994; Blum et al., 1994; Balldin et al., 1 993; Duffy et al., 1994; American Psychiatric Association Task Force, 1991, U.S.A. National Patent No. 5,189,064).   Multigene analysis of genes for psychiatric traits and other multigenic traits . Psychiatric behavior shares common genes, and once dopamine-serotony When the balance between neurons and other neurotransmitters is disrupted, the resulting brain dysfunction is widespread. (Comings, 1990a: Comings And Comings, 1991a; Winokur et al., 1970; Comings, 1994b; Comings, 1995b). other Personal traits are genetically related to dopamine transmission and other neurotransmitters May have different neurochemical and genetic substrates mediated by variability In support of the proposal (Cloninger, 1983; Benjamin et al., 1996. Epstein et al., 1996, Cl. oninger, 1991). Molecular genetic studies of DRD2, DβH, and DAT (Comings et al., 1996a) and And clinical genetic studies (Comings 1994b; Comings 1994c; Comings 1995b: Biederman Et al., 1991; Comings and Comings 1987) describe ADHD, Tourette's syndrome, behavioral disorders, O DD, dyslexia, learning disability, stuttering, drug dependence, and alcohol dependence are etiological In addition, it is said that male-dominant related spcctrum disordcrs Is shown.   During the past 20 years, a high proportion of genes for these disorders have been identified and Has been localized, cloned, and sequenced. Be identified The remaining number of such genes is decreasing, so more common multigenic disorders Interest in is increasing. What genes identify these disorders? It is often suggested that it will be difficult. This difficulty is due to psychiatry Is fully explained by a general obstacle. Exceptions to bipolar disorder possible (Risch and Botstein, 1996), manic-depressive disorder, schizophrenia, Repeated despite numerous related studies such as Autism syndrome, panic disorder, and autism There were few findings. Numerous ways to find genes in complex disorders Effort is simply based on lod score analysis, based on other families. Linkage analysis, or haplotype-related risk techniques (haplotype-relative ri single-gene si disease model (single-gene si ngle-discase model) to equipment for multi-gene disorders Was attempted (Falk and Rubinstein, 1987). Siblings affected by complex disorders Used to identify genes consisting of whole pairs of genomic screens Currently the most popular method. A nonparametric approach to chaining (Wee ks and Lange, 1988) are more suitable for complex inheritance (but Greenberg et al.). , 1996). However, the percentage of variance in which a given gene is less than 8% Multiple parent-child sets or sib pairs must be examined Not (Carey and Williamson, 1991).   Only relevant studies have a small contribution to the% variation of a given multigenic trait There is increasing recognition that they may have the power to identify genes (Risch and Me rikangas, 1996; Collins et al., 1997). Alterations in severely affected probands Those who do not have an overall association with the frequency of the candidate gene (corresponds ethnically but has no disease) Studies can identify these small effects (Weeks and Lathrop, 1995; Comings, 1996: Owen and McGuffm, 1993). DRD2, DβH and DAT genes (Comings et al., 1996j), DRD1 and DRD2 genes (Comings et al., 1 997a), OB and DRD2 genes (Comings et al., 1996d), and TS, ADHD, behavioral disorders Addition of genes in combinations of other genes in stuttering, stuttering, and related behavior Effects have been investigated. In TS syndrome, three dopaminergic genes (D (RD2, DβH, and DAT1) identified a relatively large number of TS subjects, their relatives, and And control tests have been found to be the best determined This means that TS disorders and related disorders are multigenetically inherited, and And each gene contributes only a small percentage of variation in any behavioral score (Comings et al., 1996a; Comings 1996b; Comings et al., 1996d; Comings 1 996c).   Most psychiatric disorders are multigenetic (Comings, 1996b) and Each gene contributes less than 10%, usually less than 5%, of a given behavioral variability Occupy. In both studies, the strength of the association indicates that more than one gene Increased by testing for multiplicative effects. Great for wider use of related research One of the obstacles is that many candidate genes have been cloned and sequenced. Or lack of the availability of appropriate polymorphisms in or near (Comin gs, 1994). But even when this technique or the classic chaining technique is used Positive findings from one group of researchers are often included in later studies. (Egeland et al., 1987; Kelsoe et al., 1989; Blum et al., 1990; Bolos et al. , 1990). The technique also eliminates false positives due to population stratification. Although this can occur, this is due to the haplotype relative using a large number of subjects (Comings, 1995) Can be minimized using a statistical risk procedure (Falk and Rubinstei n, 1987). The effects of these small sizes, and the difficulty in repetition, are many. Sadness over whether it is possible to identify genes involved in heavy genetic disorders Lead to speculative opinions (Moldin et al., 1997).                                Summary of the Invention   In the United States alone, 18 million alcoholics and 28 million children Alcoholics, 6 million cocaine addicts, 14.9 million other substance abuses People, 25 million nicotine addicts, 54 million at least 20% overweight, 3.5 million Childhood with ADHD or Tourette's syndrome, and about 3.7 million obsessive-compulsive bets There is a hero (compulsive gambler). We have identified alleles of the DRD2 gene. And humans for other genes associated with psychological disorders in the present invention. Genotyping is indeed rational for socially devastating problems Believe that this is the first step to a successful treatment.   The present invention first provides for the treatment of reward deficiency syndrome (RSD) behavior in a subject. A composition is provided. In certain aspects, the composition comprises at least one of the following: Contains the components of: neuropeptide opiates (amino acids, peptides, and structures) Inhibits enzymatic destruction of drugs that are either analogs or their derivatives) An opiate-destruction inhibiting amount of at least one drug; a dopamine precursor (eg, , L-Tyr, L-Phe, and L-dopa), serotonin precursors (eg, L-Trp and 5- Hydroxytryptophan) or γ-aminobutyric acid (GABA) precursor (eg, L-g Le Tamine, L-glutamic acid, and / or L-glutamate A neurotransmitter synthesis-promoting amount of at least one neurotransmitter precursor; Amount of chromium phosphate or chromium nicotinate to enhance tryptophan concentration; Compounds that release farin, enkephalin-releasing agents (peptides and Or a peptide containing D-amino acids, but not limited thereto); Receptor, μ receptor, κ receptor, σ receptor, or ε receptor Opiates of at least one compound that block the effect of opiates at some point Antagonism. Enkephalinase inhibitor, neurotransmitter precursor, opiate A type of disruption inhibitor drug, opiate antagonist, and / or chromium compound, The compounds specifically listed above are further described in the specification of the present application, And are encompassed by the present invention. In certain preferred aspects of the invention, the set The composition is used to prevent or reduce the unwanted weight of a subject. It is. In certain other aspects of the invention, the composition preferably comprises an attention deficit Used for disability, attention handling, or memory treatment. In this embodiment, note For the treatment of deficit disorder, attention deficit hyperactivity disorder (ADHD), attention processing, or memory , The composition is more preferably a small amount selected from the group of Rhodila or huvacine. Includes a neurotransmitter synthesis promoting amount of at least one neurotransmitter synthesis promoter. Book As used herein, “derivative” refers to a chemically modified compound And "analog" refers to the compound to which it is compared. And different compounds having similar properties or structures.   In certain aspects of the invention, the composition comprises any of the compositions disclosed herein. Can be used to treat RSD-related behavior. RSD behavior may be related to anxiety, anger, or drugs One or more behavioral disorders related to the well-being individual's emotions, including desire Behaviors that are related to chemical imbalances that manifest themselves. RSD actions include: Alcoholism, SUD, smoking, BMI or obesity, pathological gambling, carbohydrate glut (c arbohydrate bingeing), axis 11 diagnosis, SAB, ADD / ADHD, CD, T Includes S, family history of SUD, and obesity, which are described herein.   The invention also relates to RDS behavior (SUD, obesity, smoking, Tourette's syndrome, ADHD, schizophrenia / Avoidance behavior, aggression, post-traumatic stress syndrome, including PMS or tobacco use (Including but not limited to) treating a subject. many RDS behavior should be such that sub-disorders of a type are subsumed in these conditions. However, the present invention is not particularly limited to these obstacles. For example, attention deficit hyperactivity disorder (ADHD) As such, alcohol, drugs, obsessive-compulsive behavior, learning disabilities, and reading problems (readi ng problems), gaming, manic syndrome, phobia, panic attacks, rebelliousness Behavioral, behavioral disorders, academic problems in primary school, smoking, sexual behavior Movement, schizophrenia, somatization, depression, sleep disorders, general anxiety, stuttering, and tic disorders May manifest as harm. All these actions, and RDS actions or related to RDS Others described herein as associated with genes involved in neurological pathways Is included as an RDS action as part of the present invention. In addition, many specific obstacles Many of the clinical terms used herein are described in the Quick Reference to  the Diagnostic Criteria From DSM-IV^TM, The American Psychiatric Associat Ion, Washington, D.C., 1994, p. 358. Definition Specific disorders that can be found in this reference, and DSM-IV including anxiety disorders^TM Their code numbers in panic disorder without agoraphobia, 300.01, square Panic disorder with phobia, 300.21, agoraphobia without history of panic disorder, 300.22, special Dysphobia, 300.29, social phobia, 300.23, obsessive-compulsive disorder, 300.3, post-traumatic Torres disorder, 309.81, acute stress disorder, 308.3, general anxiety disorder, 300.02, infant Childhood hyperanxiety disorder, 300.02, anxiety disorder (by indicating general medical condition) , 293.89, including drug-induced anxiety disorder, 293.89, anxiety disorder number 300.00; attention deficit Behavioral and catastrophic behavioral disorders, including attention deficit / hyperactivity disorder (primarily, 314.00, attention deficit / hyperactivity disorder (mainly overactive-impulsive), 314.01, Attention deficit / hyperactivity disorder (mixed), 314.01, attention deficit / hyperactivity disorder number, 314. 9, behavioral disorder, 312.8, rebellious behavioral disorder, 313.81, disruptive behavioral disorder number, 312.9 And bipolar disorder, including bipolar I disorder, 296.Ox, 296.40, 296.4x, 296.6 x, 296.5x, and 296.7, bipolar II disorder, 296.89, circulatory disorder, 301.13, bipolar disorder Including harm number 296.80; depressive disorder, including major depressive disorder (recurrent), 296.3, Dysthymia disorder, 300.4, depressive disorder number 311, major depressive disorder (single episode) Eating disorders, including bulimia nervosa (nonpurging type) ), 3 07.51, bulimia nervosa (purge type), 307.51, anorexia nervosa, 307.1, eating disorder 307.50; impulsive dysregulation, including intermittent explosive disorder (Intermittent Explosive Disorder), 312.34, stealing habits, 312.32, arson habits, 312.23, pathological gambling, 312 .31, hair loss habits, 312.39, including impulsive dysregulation numbers, 312.30; personality disorders, including , Antisocial personality disorder, 301.7, avoidance personality disorder, 301.82, obsessive personality disorder, 301.4 Schizophrenia, including paranoid, 295.30, solution Mitotic, 295.10, tense, 295.20, undifferntiated, 295.90, Includes residual, 295.60, schizophrenic disorder, 295.70, schizophrenia, 295.40; sleep Disorders, including primary sleep disorders (eg, primary insomnia, 307.42, primary Hypersomnia, sleep failure including 307.42), sleep attacks, 347, circadian rhythm sleep Sleep disorder, 307.45, sleep disorder number, 307.47, parasomnia (nightmare disorder, 304.74, night terror disorder) 307.46, sleepwalking disorder, 307.46, parasomnia number, 307.47), and other mental disorders Associated sleep disorders include insomnia associated with (indicating Axis I or Axis II disorder), 3 07.42, hypersomnia associated with (indicating Axis I or Axis II disorder), 307.44, (all Other sleep disorders, including sleep disorders due to general medical conditions), 788.xx, drug inducement Conductive sleep disorders, including 788.xx; drug use disorders, including alcohol-related disorders (Eg, alcohol-induced psychotic disorder with delusions, 291.5), Alco Abuse, 305.00, alcoholism, 303.00, alcohol withdrawal, 291.8, a Delicol delirium, 291.0, alcohol withdrawal symptom delirium, 291.0, alcohol induction Conductive persistent dementia, 291.2, alcohol-induced persistent amnesia, 291.1, alcohol Addiction, 303.90, alcohol-induced psychotic disorder with hallucinations, 291.3 , Alcohol-induced mood disorder, 291.8, alcohol-induced anxiety disorder, 291.8, Alcohol-induced sexual dysfunction, 291.8, alcohol-induced sleep disorder, 291.8, Alcohol-related disorder number, 291.9, alcoholism, 303.00, alcohol withdrawal Nicotine-related disorders, including nicotine addiction, 305.10, Includes cotin withdrawal symptoms, 292.0, nicotine-related disorder numbers, 292.9, and amphetamine Related disorders, including amphetamine dependence, 304.40, amphetamine abuse, 30 5.70, amphetamine poisoning, 292.89, amphetamine withdrawal symptoms, 292.0, amphu Ethamine poisoning delirium, 292.8L amphetamine-induced psychotic disorder with delusion ), 292.11, Amphetamine-induced psychotic disorder with hallucinations, 292.12, Amphu Ethamine-induced mood disorder, 292.84, amphetamine-induced anxiety disorder, 292.89, Amphetamine-induced sexual dysfunction, 292.89, Amphetamine-induced sleep disorder , 292.89, amphetamine-related disorder number, 292.9, amphetamine poisoning, 292.89 Cannabis-related disorders, including amphetamine withdrawal symptoms, 292.0, including cannabis dependence Disease, 304.30, cannabis abuse, 305.20, cannabis poisoning, 292.89, cannabis poisoning delirium, 292.81 , Cannabis-induced schizophrenia (with delusion), 292.11, cannabis-induced psychosis Disability (with hallucinations), 292.12, cannabis-induced anxiety disorder, 292.89, cannabis-related disorder No. 292.9, including cannabis poisoning, 292.89, including cocaine related disorders, including Prevalence, 304.20, Cocaine abuse, 305.60, Cocaine addiction, 292.89, Cocaine withdrawal Letter, 292.0, cocaine addiction delirium, 292.81, cocaine-induced schizophrenia 292.11, cocaine-induced psychotic disorder (with hallucinations), 292.12, Cocaine-induced mood disorder, 292.84, cocaine-induced anxiety disorder, 292.89, coca In-induced sexual dysfunction, 292.89, Cocaine-induced sleep disorder, 292.89, Kokai Related disorder numbers, 292.9, cocaine addiction, 292.89, cocaine withdrawal symptoms, including 292.0 Only; hallucinogen use disorders, including hallucinogen addiction, 304.50, hallucinogen abuse, 305.30, Hallucinogen addiction, 292.89, hallucinogen withdrawal symptoms 292.0, hallucinogen addiction delirium, 292.81, hallucination Drug-induced psychotic disorder (with delusion), 292.11, hallucinogen-induced psychotic disorder (With hallucinations), 292.12, hallucinogen-induced mood disorder, 292.84, hallucinogen-induced failure Anxiety disorder, 292.89, hallucinogen-induced sexual dysfunction, 292.89, hallucinogen-induced sleep disorder , 292.89, hallucinogen-related disorder number, 292.9, hallucinogen addiction, 292.89, hallucinogen persistent knowledge Visual impairment (flashback), including 292.89; inhalation-related disorders, including inhalation Addiction, 304.60, inhalation abuse, 305.90, inhalation addiction, 292.89, inhalation addiction delirium , 292.81, Inhalant-induced psychotic disorder (with delusion), 292.11, Inhalant-induced Psychotic disorder (with hallucinations), 292.12, Inhalant-induced anxiety disorder, 292.89, Inclusion-related disorder numbers, 292.9, inhalation poisoning, including 292.89, opioid-related disorders, This includes opioid dependence, 304.00, opioid abuse, 305.50, and opioid medium Poison, 292.89, opioid poisoning delirium, 292.81, opioid-induced psychotic disorder (With delusion), 292.11, opioid-induced psychotic disorder (with hallucinations), 29 2.12, Opi Oid-induced anxiety disorder, 292.89, opioid-related disorder number, 292.9, opioid Poisoning, 292.89, opioid withdrawal symptoms, including 292.0; multiple drug-related disorders, including Include multidrug dependence, 304.80; tic disorders, including Tourette disorders, 307. 23, chronic motor (motor) tic disorder or chronic vocal (vocal) tic disorder, 307.22, Transient tic disorder, 307.21, tic disorder number 307.20, stutter, 307.0, autism, 2 99.00, and somatization disorders, including 300.81. In addition, other RDS disorders are known to those skilled in the art. (For example, the Novelty Seekin defined in (Clonigen et al., 1993)). g). Other obstacles are commonly known to those of skill in the art, unless otherwise specified herein. Same as knowledge, including common abbreviations.   In certain aspects of the invention, use of RDS in the treatment of RDS behavior or disorder is described. For example, the amount of each of the compounds administered daily is about 1, about 2, about 4, about 5, about 6 , About 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, About 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, About 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, About 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 55, about 60, about 65, about 70, About 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 18 0, about 190, about 200, about 220, about 240, about 260, about 280, about 300, about 325, about 350, about 375 , About 400, about 425, about 450, about 475, about 500, about 550, about 600, about 650, about 700, about 725, About 750, about 775, about 800, about 825, about 850, about 875, about 900, about 925, about 950, about 975, about 1,000, about 1,100, about 1200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1 , 800, about 1,900, about 2,000, about 2,100, about 2,200, about 2,300, about 2,400, about 2,500, about 2 , 600, about 2,700, about 2,800, about 2,900, about 3,000, about 3,250, about 3,500, about 3,750, about 4 5,000, about 4,250, about 4,500, about 4,750, about 5,000, about 5,250, about 5,500, about 5,750, about 6 6,000, about 6,250, about 6,500, about 6,750, about 7,000, about 7,250, about 7,500, about 7,750, about 8 8,000, about 8,250, about 8,500, about 8,750, about 9,000, about 9,250, about 9,500, about 9,750, about 1 0,000, about 11,000, about 12,000, about 13,000, about 14,000, about 15,000, about 16,000, about 17, 000, about 18,000, about 19,000, about 20,000, about 21,000, about 22,000, about 23,000, about 24,00 0, about 25,000, about 26,000, about 27,000, about 28,000, about 29,000, about 30,000 mg or more Can get. In addition, all amounts not specifically listed but within the ranges specified above But use And are encompassed by the present invention. For example, about 4,751, about 4,752, about 4,753 mg Are not specifically listed in the preceding text, but may be used in the present invention. .   In certain embodiments of the invention, wherein the RDS behavior is obesity, The preferred range and ingredients of the product are 460 mg DL-phenylalanine, 25 mg L-trilan With putphan, 25 mg L-glutamine, and 5 mg pyridoxal 5'-phosphate is there. In another preferred aspect of this embodiment, the subject is a subject disclosed herein. Subject has a family history of drug dependence using any method known to those of skill in the art. Tested to determine if the family history is Show potential for improvement. In another aspect of this embodiment, the treatment inhibits macrophagia You. In another aspect of the invention, the treatment inhibits craving. In a preferred aspect The composition comprises a chromium salt.   Subjects are associated with RDS behavior or psychological behavior as described herein. Alleles to be tested using molecular biological assays, and And the presence of such diagnostic alleles, the therapeutic set disclosed herein. Demonstrating subjects who are more likely to respond positively to an adult Part of the invention. In a preferred aspect of this embodiment, the subject has the following conflict: Using the methods disclosed herein for the presence of at least one of the genes, Tested genetically or by molecular biological assay: D_Two Taq I A1, B1, C1 or exon^6-7Haplotype HTR2A-C allele homozygous OB- 1875 dinucleotide repeat polymorphism is a microsatellite polymorphism on human chromosome 2 Homozygous for the <208BP allele of APO-D-Taq I 2.2 or 2.7BP, or Is the OB gene D7S1875, where detection of the above allele results in a successful response to treatment It shows that the potential for In another preferred aspect of this embodiment Wherein the composition comprises an effective amount of chromium nicotinate, and the subject The presence of the DRD2 allele is tested for the presence of the It shows that the likelihood of a successful response is improved. In another preferred aspect of this embodiment Wherein the composition comprises an effective amount of chromium picolinate and the subject has a DRD2 A2 The presence of the DRD2 A1 allele is tested for the presence of the Indicates that the likelihood of responding is improved using   In one embodiment of the invention, wherein the RDS behavior is tobacco use, the subject is , For the presence of at least one of the following alleles: Genetically or using molecular biology assays D1 (Homozygous for Dde A1), D2 (TaqI A1), D4 (VNT R2), D5 (Dinuc Reotide 13 allele range 135-159BP), DAT1 VNTR (10/10), DβH (Taq1 B1 allele) Gene), wherein detection of the allele may successfully respond to treatment. Indicates that performance is improved.   Another embodiment of the present invention, wherein the RDS behavior further comprises autism, Tourette's syndrome or ADHD. In embodiments, the subject has a presence of at least one of the following alleles: Genetically tested or molecular organisms using the methods disclosed herein. Tested by a biological assay: D1 (homozygosity for Dde1 A1), D2 (TaqI A1), D4 (VNTR 2), D5 (dinucleotide 13 allele range 135-159BP), DAT1 VNTR (1 0/10), DβH (Taq1 B1 allele), MAOA (X), where detection of the above allele Indicates that the likelihood of a successful response to the treatment is improved. This embodiment In certain preferred aspects of the composition, the composition comprises an effective amount of Rhodila or fuvadin. Including.   In one embodiment of the invention, wherein the RDS behavior is a pathological betting, the subject A method disclosed herein for the presence of at least one of the following alleles: Tested genetically or by molecular biological assays : D1 (homozygous for Dde1 A1), D2 (Taq A1, B1, C1), where the above alleles Detection of the gene indicates that the likelihood of a successful response to the treatment is improved.   RDS behavior is increasingly associated with pathological violence, disruption / avoidance (SAB), Habit, anger, hostility, post-traumatic stress disorder In embodiments, the subject has a presence of at least one of the following alleles: Have been genetically tested or produced using the methods disclosed herein. Tested by physical assay: D2 (TaqI A1, B1, C1, exon^6-7), DAT1 (VNTR 10/10), homozygous for mNOS- ≦ 201 BP, where Indication indicates that the likelihood of a successful response to the treatment is improved.   In another embodiment of the invention, wherein the RDS behavior is PMS, the subject is a DAT1 VNTR (10/10), D_TwoTaq A1, B1, C1, exon^6-7Alleles from haplotypes, or Is DRD1, DRD2, DRD4, HTT, HTRIA, TDO2, DβH, MAO, COMT, GABRAB, GABRB3, P Presence of at least one allele from the ENk, ADRA2A or ADRA2C gene Can be genetically tested or analyzed using the methods disclosed herein. Tested by an offspring biological assay, wherein detection of the allele is It indicates that the likelihood of a successful response to the response is improved.   The invention further relates to pairs of alleles from the group including, but not limited to: By detecting at least one of the progenitors, the genetic predisposition of the subject is reduced. Provides further ways to determine at least one RDS action: DRD1, DRD2 , DRD3, DRD4, DRD5, DAT1, HTT, HTR1A, TDO2, DBH, ADRA2A, ADRA2C, NET, MA OA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, CRF, HTRIDβ, H TR2A, HTR2C, interferon gamma, CD8A, or PS1 gene, where allele The child diagnoses RDS behavior. In one embodiment of the invention, the subject is a MAOA For at least one occurrence that is a VNTR polymorphism in a gene allele, Genetically tested or molecular biological assays using the methods disclosed in B, where the presence of the allele indicates that the subject has RSD behavior (manic , OCD, sexual behavior, sleep, elementary school behavior, gambling, learning, carelessness, ADHD, ADDR, impulse, M DE, CD, hyperactivity, phobia, schizophrenia, generalized anxiety, somatization, drugs, IV drugs, Reading, including the use of ODD, tics, alcohol, or tobacco) Diagnose having a predisposition.   In another embodiment of the invention, the subject has at least one DRD2 gene A1 pair. Allele, DAT1 gene, VNTR 10/10 allele, or DβH gene B1 allele The presence may be genetically tested using the methods disclosed herein, or Or by a molecular biological assay, wherein the presence of the allele is If the subject has a genetic predisposition to RDS behavior (including disruption or avoidance) Diagnose.   In another embodiment of the invention, the subject has an increased number in the CNR1 gene. (ATT)_nUsing the methods disclosed herein for the presence of triplet repeats Tested genetically or by a molecular biological assay, where , The presence of the allele will signal the subject to RDS behavior (including drug use). Is diagnosed as having a predisposition.   In another embodiment of the invention, the subject has an increased number of D7 in the OB gene. For the presence of S1873, D7S1875, D7S514, or D7S680 dinucleotide repeats, Genetically tested or molecular biology using the methods disclosed herein Test, where the presence of the allele indicates that the subject Movement (obesity, anxiety, depression, mental illness, hostility, paranoia, ideation, compulsiveness, gross symptoms (s ymptom total), general symptom index, new exploration (novelty see king), including overall total, nervousness, and pruritus Diagnose a genetic predisposition. In this embodiment, the D7S1875 dinucleotide The allele that is a repeat of the allele is preferably longer than 225 bp and Preferably, the gene is present in both copies of the CNR1 gene. In this embodiment In the above, another allele to be detected is the D of the DRD2 gene._TwoA1 allele Is also preferred. In this embodiment, it is also preferred that the RDS behavior is obese. No.   In another embodiment of the present invention, the subject has a DRD2 gene D_TwoExistence of A1 allele Is genetically tested using the methods disclosed herein, or Is tested by molecular biological assays, where the presence of the allele is Specimen was tested for RDS behavior (Tret syndrome, manic symptoms, rebellious behavior, sexual behavior, ADHD-R, division Illness, ADHD, tics, major depression, behavior, stir, obsessive-compulsiveness, somatization, alcohol abuse, Diagnosed with a genetic predisposition to learning and sleep problems).   In another embodiment of the present invention, the subject has a Taq A1 allele of the DβH gene. The presence may be genetically tested using the methods disclosed herein, or Or by a molecular biological assay, wherein the presence of the allele is Subject is subject to RDS behavior (Tret syndrome, ADHD, smoking, learning, primary school, ADHD-R, rebellion Sexual behavior, tics, mania, alcohol, reading, substance abuse, sleep, stir, obsession Diagnosed with a genetic predisposition to sexuality, somatization, and major depression). Book In embodiments, the allele detected is the Taq B1 allele of the DβH gene or And Taq A1 alleles and RDS behavior are Tourette syndrome Is preferred.   In another embodiment of the invention, the subject has 10 alleles of the DAT1 gene. Is genetically tested using the methods disclosed herein, or Tested by a molecular biological assay, wherein the presence of the allele is Body, Tourette syndrome, autism, somatization, alcohol, ADHD-R, major depression, depression, For obsessive-compulsiveness, general anxiety, mania, rebellious behavior, sex, reading, and ADHD Diagnose a genetic predisposition.   In another embodiment of the present invention, the subject has 10 alleles of the DAT1 gene, DβH Taq A1 allele of gene or D of DAT2 gene_TwoAbout existence of A1 allele Genetically tested or molecular organisms using the methods disclosed herein. Tested by a biological assay, wherein the presence of the allele HD, stuttering, ADHD-R, rebellious behavior, tics, actions, obsessive-compulsive disorder, mania, alcohol Genetics for general anxiety, schizophrenia, sleep, sex, drugs, and major depression Diagnose a predisposition.   In another embodiment of the invention, the subject has the presence of the DdeI allele of the DRD1 gene. Is genetically tested using the methods disclosed herein, or Is tested by molecular biological assays, where the presence of the allele is Specimens should be treated with alcohol, smoking, compulsive eating, tics, gambling, drugs, reading, Papping, rebellious behavior, major depressive episode, schizophrenia, ADHD, behavioral disorder, obsessive-compulsive disorder Diagnose a genetic predisposition to harm, and mania.   In another embodiment of the invention, the subject has a TaqIA1 allele and a DRD2 gene. Using the methods disclosed herein for the presence of the TaqI A2 allele of the gene, Tested genetically or by a molecular biological assay, where , The presence of the allele may indicate that the subject has rebellious behavior, behavioral disorders, eating, smoking, Diagnosis of a genetic predisposition to Haku, ADHD, obsessive-compulsiveness, mania and alcohol You.   In another embodiment of the invention, the subject has 11 or 22 genotypes of the DRD1 gene. The presence may be genetically tested using the methods disclosed herein, or Or by a molecular biological assay, wherein the presence of the allele is Diagnose the subject as having a genetic predisposition, including Tourette's syndrome, smoking, and gambling I do. In this embodiment, the allele detected is the DdeI allele of the DRD1 gene. Preferably, there are two copies per genome of the gene.   In another embodiment of the invention, the subject has a presence of 11 genotypes of the DRD1 gene. And genetically tested or molecularly tested using the methods disclosed herein. Tested by a biological assay, wherein the presence of the allele , Rebellious behavior, behavioral disorders, obsessive-compulsive eating, smoking, gambling, ADHD, mania, stutter, obsessive-compulsive Diagnose having a predisposition including gender and schizophrenia.   In another embodiment of the invention, the subject has the presence of the DdeI allele of the DRD1 gene. Is genetically tested using the methods disclosed herein, or Is tested by molecular biological assays, where the presence of the allele is Specimens, gambling, smoking, compulsive eating, rebellious behavior, major depressive episodes, ADHD, behavior Diagnosed as having a genetic predisposition including disability, schizophrenia, obsessive-compulsiveness, mania, and alcohol Refuse.   In another embodiment of the invention, the subject has 11 or 22 genotypes of the DRD1 gene. The presence may be genetically tested using the methods disclosed herein, or Or by a molecular biological assay, wherein the presence of the allele is Subjects may be exposed to alcohol, smoking, obsessive-compulsive eating, tics, gambling, drugs, reading, Diagnosing a genetic predisposition to shopping, gambling, and elementary school problems .   In another embodiment of the invention, the subject is tryptophan 2,3 dioxygena. The presence of the intron 6 G → A polymorphism in Genetically or using molecular biology assays Where the presence of the allele indicates that the subject has a genetic Diagnose a predisposition.   In another embodiment of the invention, the subject is tryptophan 2,3 dioxygena. The presence of the intron 6 G → T polymorphism in the inose gene Genetically or using molecular biology assays Where the presence of the allele indicates that the subject has ADHD, alcoholism, Diagnose a genetic predisposition, including substance dependence and morbid gambling.   In another embodiment of the invention, the subject is tryptophan 2,3 dioxygena. As disclosed herein, the presence of an intron 6DGGE polymorphism in the Genetically or using molecular biology assays Where the presence of the allele indicates that the subject has ADHD, alcoholism, Diagnose having a genetic predisposition including substance dependence, morbid gambling, and depression.   In another embodiment of the invention, the subject is an ADRA2C dinucleotide repeat polymorphism. Disclosed herein for the presence of low base pair allele (≦ 181 bp) polymorphisms of Genetically tested using methods or tested by molecular biological assays Where the presence of the allele indicates that the subject has a genetic predisposition, including drug use. Is diagnosed as having.   In another embodiment of the invention, the subject is an ADRA2C dinucleotide repeat polymorphism. For the presence of two high base pairs that are alleles for ≦ 183 bp of Genetically tested or molecular biological assays using the methods disclosed in Test, where the presence of the allele indicates that the subject Diagnosis of having a genetic predisposition including use.   In another embodiment of the invention, the subject has a presenilin 1 (PS1) polymorphism. Use the methods disclosed herein for the presence of two homologous alleles. That are genetically tested or tested by molecular biological assays Here, the presence of the allele includes subjects with alcohol and tobacco use. Diagnose a genetic predisposition. In this embodiment, the allele detected is Two homologs greater than the 80 bp CA dinucleotide repeat polymorphism of the PENK gene Preferably, it is an allele.   In another embodiment of the present invention, using the methods disclosed herein, Are subjects genetically tested for the presence of the short GGC allele of the gene? Or molecular biology assays where the presence of this allele is Is available for subjects with a genetic predisposition, including CD, ODD, or hyperactivity. It is absolute.   In another embodiment of the present invention, using the methods disclosed herein, DR Subjects are genetically tested for the presence of the D2 allele or Tested by a physical assay where the presence of this allele is Genetics, including B-type behavior in leukemic, cocaine addicts, or RDS probands Diagnostic for subjects with a predisposition.   The present invention further provides DRD1, DRD2, DRD5, DAT1, HTT, HTR1A, TDO2, DBH, ADRA2A. , ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR , CRF, DRD3, DRD4, HTR1Dβ, HTR2A, HTR2C, interferon-γ, CD8A, Or at least one allele associated with a group consisting of the PS1 gene Providing a method for determining a genetic predisposition to a polygenic trait, comprising: . In one embodiment of the invention, the polygenic trait is ADHD, Is DRD1, DRD2, DRD5, DAT1, HTT, HTR1A, TDO2, DBH, ADRA2A, ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, or CRF inheritance Related to the child. In another embodiment, the polygenic trait is susceptible to ADHD. Missing, alleles are DRD3, DRD4, HTIR1Dβ, HTR2A, HTR2C, Associated with the elongon-γ, CD8A, or PS1 gene.   In another embodiment of the invention, the polygenic trait is OOD and the allele is , DRD1, DRD2, DRD3, DAT1, HTT, HTR1A, HTR2A, HTR2C, DBH, ADRA2A, ADRA2C , MAOA, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, or CD8A gene Related to   In one embodiment of the invention, the polygenic trait is tic, Children are DRD1, DRD5, HTR1A, HTR1Dβ, HTR2C, TDO2, DBH, ADR2C, COMT, GABRA3 , CNR1, or CHRNA4 gene.   In another embodiment of the invention, the polygenic trait is LD and the allele is Associated with DRD1, HTR2C, TDO2, DBH, ADR2A, ADR2C, MAOA, CNR1, or CNRA4 gene Connect.   In one embodiment of the invention, the polygenic trait is LDL, Is associated with the HTT, OXYR, DRD2, or PS1 gene.   In one embodiment of the invention, the multigenic trait is longevity. Alleles are associated with the PS1, OXYR, or APOE gene.   The invention further comprises the step of identifying the trait to be studied, Creating a scale to measure severity: at least one that can contribute to the trait Selecting a candidate gene, identifying at least one polymorphism associated with the candidate gene Identifying, correlating polymorphic allelic patterns with scale, and The association of pattern and allelic patterns with the correlation of candidate genes to traits The steps provide a method for developing a diagnostic, multigene assay. Allelic patterns positively associated with the trait are added to each other and Diagnostic for the susceptibility of subjects with child traits Form a gene assay. Allele patterns negatively associated with traits Is added and is diagnostic for the lack of prevalence in subjects with polygenic traits Forming a multigene assay is also part of the present invention.   In one embodiment of the present invention, the candidate gene is DRD1, DRD2, DRD5, DAT1, HTT, HTR1A, TDO2, DBH, ADRA2A, ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, CRF, DRD3, DRD4, HTR1Dβ, HTR2A, HTR2C, Including but not limited to interferon-γ, CD8A, or PS1 gene .   In another embodiment of the invention, the polygenic trait is ADHD, lack of ADHD, ODD, C D, LD, tics, substance abuse / addiction, smoking, osteoarthritis, cholesterol levels Including, but not limited to, elevated LDL levels, or longevity.   In one embodiment of the invention, the polygenic assay for ADHD comprises DRD1, DRD2, DRD5, DAT1, HTT, HTR1A, TDO2, DBH, ADRA2A, ADRA2C, NET, MAOA, COMT , GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, or CRF gene Detection of at least one allele.   In another embodiment of the invention, the polygenic assay has reduced ADHD It is related to the lack of morbidity, including DRD3, DRD4, HTR1Dβ, HTR2A, HTR2C, At least one allele associated with the terferon-γ, CD8A, or PS1 gene Detecting the offspring.   In one embodiment of the invention, the polygenic assay is for OOD. Yes, DRD1, DRD2, DRD3, DAT1, HTT, HTR1A, HTR2A, HTR2C, DBH, ADRA2A, ADR A2C, MAOA, GABRA3, GABRB3, CNR1, CHRNA4, NMDAR1, PENK, AR, or CD8A Detecting at least one allele associated with the gene.   In another embodiment of the invention, the polygenic assay is for tics Yes, DRD1, DRD5, HTR1A, HTR1Dβ, HTR2C, TDO2, DBH, ADR2C, COMT, GABRA3 Detects at least one allele associated with the CNR1, CNR1, or CHRNA4 gene Process.   In one embodiment of the invention, the polygenic assay is for LD. DRD1, HTR2C, TDO2, DBH, ADR2A, ADR2C, MAOA, CNR1, or CHRA4 gene Detecting at least one allele associated with   In another embodiment of the present invention, a multigene assay measures elevated LDL levels. At least one associated with the HTT, OXYR, DRD2, or PS1 gene. Detecting the two alleles.   In one embodiment of the invention, the multigene assay is for lifespan. Yes, at least one allele associated with the PS1, OXYR, or APOE gene Detecting.   In another embodiment of the invention, the polygenic assay is for osteoarthritis COL2A1, COL2A1, COL2A1, COL9A1, COL9A1, AGC1, IGFL1, IGF1, IGF1R , IGF1R, IGF2, IGF2R, TGFB1, TGFB2, IL1A, IL1B, IL1R1, IL1RN, MMP9, TIMP Detect one or at least one allele associated with the vitamin D3 gene The method further includes a step.   As used herein, the term "a" or "an" or "the" may mean one or more It is understood that may mean one or more.                             BRIEF DESCRIPTION OF THE FIGURES   The following drawings form part of the present specification and further illustrate certain aspects of the present invention. Included to prove. The present invention is not limited to the specific embodiments set forth herein. Better by referring to one or more of these drawings in combination with the description Can be understood.   FIG. "Super control (normal)" and severe "RDS" proband DRD2 gene. Linear trend analysis to compare across the indicated groups, p <0.00000 Had one. The following are the groups selected by the computer:   Group I (C1): alcoholism, drug use disorders, polydrug dependence, obesity and Family history of drug dependence, nicotine dependence (smoking) BMI greater than 25, carbohydrate glut, self Autism, Tourette's disease, ADIID, Axis II, pathological gambling, post-traumatic stress syndrome Was carefully evaluated. We used DS to evaluate drug use disorders. MIV criteria were used (N = 11).   Group II (C2): Exclusion criteria similar to Group I (N = 6).   Group III (C3): Includes positive family history of drug use disorders and obesity Exclusion criteria similar to Groups I and II, except that   Group IV (C4): Group I except for smoking behavior (nicotine dependence) Exclusion criteria similar to, II, HI (N = 21).   Group V (C5): Group I except including benzodiazepine abuse / dependency Exclusion criteria similar to, II, III, IV (N = 31).   Group VI (C6): Drug use disorders (ie, alcohol and cocaine) Exclusion criteria similar to Groups I, II, HI, IV, V except included (N = 74).   Group VII (C7): Group I, II, III, except that it contains more than 25 BMI Exclusion criteria similar to W, V, VI (N = 140).   Group VIII (C8): Concurrent drug use disorders (alcohol and cocaine Same as Groups I, II, III, IV, V, VI, VII, except for over 25 BMIs with abuse Exclusion criteria (N = 31).   Group IX (C9): Multidrug dependence of concurrent disease (ie, alcohol and coca Group I, II, III, IV, V, VI, VII, VII except for more than 25 BMI with Exclusion criteria similar to I (N = 11).   In addition, the inventors have also previously described the literature (Blum et al., 19 90, Blum et al., 1991, Noble et al., 1992, Parsian et al., 1991, Comings et al., 1991, Smith Et al., 1992, Amedeo et al., 1993) genotyped and 18.5% D2A1 prevalence A total of 286 (N = 286) healthy white (L1) men and women (alcohol and And nicotine abuse only, and in some cases Screened). Furthermore, the present inventors have a total of 714 (N = 714 ) D2A1 incidence rate 25.9 (only for alcohol or multi-drug dependence) (Blum et al., 1990, Parsian et al., 1991, Comings et al., 1993, Noble 1994, Amedeo et al., 1993, Comings et al., 1994, Noble 1993, Schwab et al., 1991, U. hl et al., 1992, O'Hara et al., 1993, Uhl et al., 1992)). ) Was included. In addition, we also note that the D2A1 prevalence of 32.9 (see (Bolos et al., 1). 990, Grandy et al., 1989, Gelernter et al., Uhl 1992, Goldman et al., Finns 1994, Nothe n et al., Noble et al., 1994, Jonsson et al., 1993, Hedebrand et al., 1993, O'Hara et al., 1993) 980 (N = 980) subjects (L3) Was included.   FIG. Phencal for weight loss^TMEffect. This figure shows PHENC after a two-year period AL^TMGroup and non-PHENCAL^TM3 shows a comparison of body weight in both groups. Two years of research Finally, PHENCAL^TM(N = 130) received PHENCAL^TMHas been administered Average 23.5% body compared to 52.8% in no control group (n = 117) There was a heavy excess (p <0.0001).   FIG. Allele distribution of the MAOA VNTR polymorphism (total number of alleles = 768).   FIG. Additional effect of increasing number of variant additional genes on ADHD score. This Effect of a gene having only 4 or 5 modified genes from 1.0 to 15 There was a gradual increase in the number of genes with mutant genes up to 25.0. ADHD score The p-value of a linear chi-square test of stepwise increase in^-8Met.   FIG. 5 shows the additive and subtractive effects of all 29 genes on ADHD score, As well as additive effects of additional genes only. The white square at the bottom shows the observed score. For each gene assigned a random score matched to frequency R^TwoIndicates a value. r^TwoThe incremental effect of the value is indicated by a white square and The additional effect of using only the correlation of is indicated by the square containing the cross. That point Lines marked with an “x” are additional genes, whose points are black dots The marked lines are the additive and subtractive genes. Both additive and subtractive Use the final r^TwoWas .0001. Of additive random genes Only use the final r^TwoWas .0004. Neither was significant. Further Into, replaceable r^TwoWas about .008 tall in the random PENK gene. This means that when the final random additional gene (CD8A) is added, lowered.   FIG. Add all 29 genes to the split half of the sample (n = 166) And subtractive effects. Some genes are additive and in both sets They are subtractive, some are additive in one and subtractive in the other. Black dots indicate group 1 data, black squares indicate two group II data,   FIG. DSM-IV ADHD symptoms for subjects who meet the DSM-IV diagnostic criteria for ADHD Distribution of the number of mutated genes in subjects without symptoms.   Figure 8. Cholesterol and L of four genes, HTT, OXYR, DSD2, and PS1. Additive effect on DL blood levels. This figure shows that MAA technology was used to study 154 subjects. When combined, identified four genes, p = 2.0 × 10^-FourHave To give significant results. Filled circles indicate cholesterol data, open circles indicate data Shows data for low density lipoprotein.                          Description of an exemplary embodiment Multigene diagnosis of RDS and other polygenic traits   We Reward Various Psychological Disorders to a Common Biological Substrate, Some Behavior "Hard-wired" in the brain that provides satisfaction in the process ) ", We think that they are linked. The present inventors, in the present invention, Alter intracellular signaling in the nucleus accumbens or other limbic reward areas, Innate chemical imbalances reduce happiness, anxiety, anger or negative emotions. Advocates that cravings for drugs that can be reduced (ie alcohol) can make up . This chemical imbalance has manifested itself as one or more behavioral disorders. For this reason, the term “reward deficiency syndrome” was created (Blum et al., 1996a).   In reward deficiency syndrome or RDS, genetic deficiencies in the reward pathway Genetic testing is best understood as a genetic disorder and testing for a large number of Requires testing. The present invention relates to the predisposition to RDS and the following: dopaminergic gene D RD1, DRD2, DRD3, DRD4, DRD5, dopamine transporter gene (DAT1); Rotonin gene HTT, HTRA, HTRDb, HTRA, HTRC, tryptophan 2,3-hydroxa Rase (TDO2); norepinephrine gene, DβH, ADRAA, ADRAC, NT; Luamine metabolism gene, MAOA, COMT; GAGA gene, GABRAA, GABRAB, cannabinoi (Canabinoid) receptor gene, CNR; nicotinic cholinergic, CHRNA; NM DA receptor gene, NMDAR; Enkephalin gene, PENK; Androgen receptor Puter gene, AR; interferon-γ gene, INFG; CDR; presenilin-, P S-; CRF gene, CRF, obesity gene (OB), leptin receptor gene; serotoni HTR1A receptor gene, serotonin receptor (5HT2R) gene, catechol -O-methyl-transferase (COMT) gene, neuronal nitric oxide sinter Gene (nNOS1a), apolipoprotein-D (APO-D and uncoupling) (Uncoupling) proteins, including but not limited to (UCP1 and UCP2), Correlations between multiple genes and alleles were identified.   The nature of RDS and related behaviors are so complex that many environmental factors are important. Gender is one 100% gene or environmental factor that certainly contributes as a determinant Deny the possibility of In general, the "reward cascade model" is In this case, we believe that if the More genes can be responsible for the overall mismatch rate in one RDS subtrait But has little or no relationship to another RDS action. Be cautious to point out.   Improved genotyping techniques use a genetic approach to It has made it commercially possible to map genes involved in the pathogenesis of disease. Many Of disease genes within the family of disease traits using random marker loci Identified by a linkage analysis approach testing simultaneous separations. Most of these are A gene involved in unigenic Mendelian disease with a simple pattern of transmission (Weeks and Lathrop, 1995). Today, human geneticists say, for example, hypertension, sugar Multiple RDS behaviors such as urinary disease, heart disease, multiple sclerosis, arthritis and obesity He has begun researching the genetics of causative diseases. Multifactorial diseases affect each other and the disease Triggered by multiple genes that interact with environmental factors that create a genetically sensitive gradient Be woken up. The higher degrees and types, or the interactions between these genes, are linked. It strongly influences the chance of detecting genes by strand analysis studies. Even if the top However, if genetic heterogeneity is maintained, several distinct loci may be Independently cause traits, chances of success may be low. Complex like RDS For various diseases, traditional LOD score analysis does not appear to be very powerful. Because it accounts for most of the genetic variation, the consequences of a single, major disease Assuming the presence of a locus (with a particular mode of inheritance), and now this It is known that S is not true, and therefore related studies are more powerful and And preferred.   Alcohol dependence itself or RDS behavior such as TS and ADHD One important gap in the prior art in attempting to find Most researchers, including the present inventors, have focused on the single gene approach. And therefore a small contribution to the overall mismatch (more about the DRD2 allele) Una) could only be identified. For example, for TS, most research Studies also use linkage models with autosomal dominant inheritance, with reduced expression rates. Studies, but no associations, and, to date, virtually 100% Despite "outside," this approach was useless. The present inventors have determined that RDS To be a multigene region disorder with genes contributed by one parent Came. Lod score linkage studies attempted in disorders that are polygenic in nature In some cases, too many errors in labeling occur, effectively defining a phenotype. Negative lod scores can be obtained even with the genes involved You. In addition, if the disorder is inherited polygenic, specific genes by linkage analysis Role has been ruled out as in the case of the DRD2 gene and is no longer effective (Devo r et al., 1994; Gelernter et al., 1990).   In the present invention, reference is made in some cases to a multigene cell as a multigene. Is made to a single gene. In the past decade, we have been studying behavioral and divine We have explored the potential role of dozens of genes in a range of transgenic phenotypes . Based on the calculation of the correlation coefficients, we have explained, regardless of the level of importance, The percentage of discrepancies for QTVs ranges from 0.5% to 2.5%, depending on the polymorphism specified. Find out what is. Due to the low level effect of this given polymorphism on the trait Association studies may be the only viable way to identify multigenic effects. Many As the proportion of phenotypes describing genes decreases, the difficulty in identifying their effects But The number of subjects that have increased and must be studied also increases. Related research One criticism was that control was drawn from different racial or ethnic groups. The presence or difference of the frequency of the gene in such a group Results can be obtained. This is achieved by using haplotypes. Can be theoretically excluded. A relatively dangerous technique for unpleasant markers. Where the frequency of one allele ranges from 0.1 to 0.2 and is Genes are described as less than 20% mismatched, and the power of this technology is severely restricted. Limited. In the end, one of the opponents of advocates of the relevant approach is, inter alia, DRD2 research. Carefully screen controls to determine the number of already associated RDS Failure to exclude behavior (eg, SUD, TS, ADHD, CD, SAB), and testing Conditions can lead to false assumptions that they are not relevant (Blum et al., 1995, Blum et al., 1997).   However, a variant analysis of some available data suggests that this association is robust. (Cloninger, 1991; Gorwood et al., 1994; Noble and Blum K, 1993). Pato et al., 1993; Cook and Gurling, 1994; Uhl et al., 1993; Blum et al., 1995; Blum. Et al., 1997). DRD2A1 allele associated with alcohol dependence (but this gene An important factor in the study of (also held for other RDS behaviors) is the use of The type of competitive control used. Use the controls used earlier Analysis showed that the prevalence of the A1 allele was Significantly more than assessed for alcohol dependence and other related factors High (Uhl et al., 1993; Noble et al., 1994a). The problem is Neiswanger Et al., 1995 and in a recent study by Hill and Nyswander, 1997. Was. They use the "Super Normal" control to A strong association of A1 allele with call dependence was found. This group Use of an evaluated control group such as Perhaps more important than the stratification of the population, Assume description.   Super control. We are the Prince of New Jersey Evaluated 184 probands in a psychiatric and medical clinic, where he Carefully evaluated the controls so that each individual had many RDS behaviors ( Alcohol dependence, SUD, smoking, BMI or obesity, pathological gambling, carbohydrate glut, ax excluded from is11 diagnosis, SAB, ADD / ADHD, CD, TS, family history of SUD, and obesity) Was then genotyped for TaqID2A1, and 32.9% were DRDA1 alleles Unlike the unscreened Caucasian population, which has a gene, from 30 people Only one of the individuals that meets the inclusion criteria holds the D2A1 allele. (Or only 3.3%) was found (see Figure 1) . In fact, when all groups were compared, they were very well assessed A1 + increase in multiple drug dependence group (severe) compared with control The progressive percent (%) at significantly higher allele rates in (X2 = 78.8, df = 1, p <0.000001).   One important embodiment of the present application is to use a number of genetic variants in the RDS line to be diagnosed. Includes methods to detect alone or in combination based on individual contributions to motion. Book The inventors have found that by utilizing combinations of genes, and for that particular multiplicity. Individuals at risk in some manner by detecting typology or actual mutations Can be identified, whereby only one gene has dopamine Original publication suggested using DNA based on detection of D2 receptor gene That higher accuracy can be achieved than if it were detected as in a granted patent. I found it. To provide a clearer overview of the magnitude of this possibility, some The gene is suspected as being involved in the reward pathway. This is involved in the reward path Neurotransmitters, related genes reported, polymorphisms and genetic defects Illustrate the hypothetical effects it has on behavior and other impulsive, addictive behaviors, We believe that these and possibly many other unidentified genes are It suggests that it constitutes a complete variant map of S. This is time and gene Studies that affect other neurotransmitters have been added to a multigene set. And other psychiatric disorders (especially the "reward" and behavior of the present invention) Is also polygenic and readable using this technique. Work as a basis to consider what is. In fact, many chromosomal loci and specific It is possible that a marker or gene will be discovered in the near future, but here MU LTIPLEX GENESCAN^TMDevelop many already associated genes, reward deficits Characterized by the inventors as including syndromes and other polygenic traits It is intended to detect in impulsive, compulsive, and addictive behavior. further, Diagnostic methods for polygenic traits including RDS include multiple additive association (Multiple Ad ditive Association (MAA) technology, which was developed by the present inventors.   The process of multiple additivity association (MAA) technology. Particular embodiments may be used to diagnose RDS-related disorders. Demonstrates the use of MAA technology to build the assay. However, we have: Gives many examples of independent psychiatric disorders, and MAA technology It illustrates that genetic disorders and all polygenic traits can be generalized. Therefore, We consider MAA technology as a procedure for all polygenic disorders . Polygenic disorders each explain only a small percentage of phenotypic variability Attributable to the additive effects of many genes. Those Is present to varying degrees in all individuals. A polygenic disorder is a single genetic disorder It is more common than harm and affects 1-20% of the population. Some examples are Hypertension, obesity, most psychiatric disorders, multiple sclerosis, lupus lupus erythematosus , Osteoporosis, coronary artery disease, rheumatoid arthritis, osteoarthritis, weight, height, blood pressure, age ( Life span), part by psychological traits and more than one gene or allele Any other trait that can be determined. Below is how MAA technology is done Or teach.   The MAA technology of the present invention has the following unique additional properties. First, it can be tested Dramatically increase the number of genes to thousands. MMA technology is all quantitative or The dichotomous trait is replaced by the correlation coefficient (r) and percent variance (r2) instead of the trait itself To place them on the same scale. MMA technology is an individual genetic When a child is added, the gene is additive (increase in r and r2) or Incorporate concepts that can be either subtractive (decrease in r and r2). MAA technique Surgery can use this increase or decrease to play a role in the disorder or trait. From these genes (because they are subtractive), the disorder or trait These genes play a role in (because they are additive) ). MAA technology uses only additive genes for reanalysis, Estimating r2, the total percentage of variance, explained by identifying the arithmetic gene I will provide a. Rather than testing one gene at a time, add multiple genes By testing different effects, MAA technology can simply test genes, Core (lod score), sib pair (sib pair), haplotype relative risk (Falk and And Rubinstein, 1987) and transmission disequilibrium  test) (Spielman and Ewens, 1996) Have a stronger ability to identify genes involved in MAA technology once The p-value for a related study testing one gene at a time is Shows little relevance to quality involvement. MAA technology is as follows Specific steps are unique to the technology. .   Step 1. The first step involves a polygenic disorder or trait (ie, attention deficit hyperactivity Sexual dysfunction (ADHD), depression, cholesterol levels, weight, obesity, longevity, blood pressure, frequent occurrence Sclerosis, or other that is polygenic or suspected of being polygenic Any disorder or trait) to be studied. Identified If not, DIS (Diagnostic Interview Schedule) (Robins et al., 1981). Or structured diagnostic questions such as SCID (Williams et al., 1992) Used to apply the criteria, have a known psychological trait or are polygenic Create a psychiatric diagnosis of the suspected individual. We have found that most published Recent DSM versions may be used to create such diagnostics It is contemplated that older versions may be used as well.   Step 2. The second step is to set up a scale to measure the severity of the polygenic disorder. Is to determine. This can be a quantitative trait or a dichotomous variable (QT or Or DV). For example, when blood pressure is studied, the quantitative scale is flaccid blood pressure. Yes, if height is studied, it can be used in inches or centimeters, If fullness is studied, the scale can be weight or BMI, where depression is studied. If so, the scale can be the number of positive DSM-IV criteria for depression, and so on. Bisection traits can also be used. For example, 200 controls and 200 When subjects with multiple sclerosis are studied, the control is Subjects that are cored and have multiple sclerosis are scored = 1. Trait, The score for the phenotype, or QTV, refers to the magnitude of the number of traits. For example , I weigh 200 lbs and my weight score is 200. I am a cholesterol level If I have a bell 250, my cholesterol score is 250, and so on. Remains Scores for genes are based on which phenotype has the smallest, intermediate, or largest phenotypic effect Assign a "score" of 0, 1, or 2 to the phenotype, depending on whether I mean   Step 3. This third step is to identify candidate genes to be tested. Examples include ADHD, rebellious behavioral disorders, behavioral disorders, propensity disorders, alcohol 29 candidate genes selected for dopamine, serotonin, norepinephrine It is a gene that plays a role in regulating neurotransmitters including phosphorus and GABA. And One skilled in the art will recognize that any gene can potentially contribute to a polygenic trait. recognize. Selection of candidate genes or sets of genes to be used in MAA technology Is a gene that has some metabolic or physiological relationship to the trait being examined, It can be facilitated by choosing first. Public library or Genbank (N (available from the ational Center for Biotechnology Information) Described or published in the scientific literature available in computerized databases Any indicated gene or gene allele is a candidate for use in MAA technology A diagnostic or prognostic assay for a particular trait Create a file. One of skill in the art will recognize candidate genes for most polygenic traits and disorders. Other sources of genetic information (personal knowledge, Is not publicly available or contains publicly available knowledge) Recognizing that, such sources can be used in the performance of the MAA method.   Candidate genes involved in polygenic traits, such as height or susceptibility to osteoporosis Examples of involvement in bone and / or connective tissue formation, growth, and / or regulation Is a gene that Another trait that can be evaluated is obesity, and the candidate gene is In addition to these genes, candidate genes, OB gene, OB receptor gene, Includes transpeptide Y gene and neuropeptide Y receptor gene. Like blood pressure For noble traits, reasonable candidate genes are norepinephrine, epinephrine, It is a gene related to teroid and renin metabolism.   In the examples of the present invention, various genes believed to contribute to the polygenic trait chosen. Of particular interest are genes that may contribute to RDS behavior. Was. Criteria for selection of genes may be signs of their involvement, signs from the literature, one or more. Signs in RDS behavior or other polygenic traits of interest and / or Indications of experimental data by the inventor described in the above section. We believe that genes or Or the relationship of a polymorphism to a given trait is used in diagnostic assays for the trait. And the purpose of the gene and / or its specific polymorphisms For inclusion in MAA diagnostic assays for polygenic traits in rice Provide gender guidance. Traits are related to RDS for genes or polymorphisms. There is no need to be linked.   DRD1 gene. This particular gene was identified in preliminary studies by the inventors. Is not associated with severe alcohol-dependent probands, as compared to controls, and therefore These further findings with larger samples were surprising. In this study, testing for both DRD1 and DRD2 dopamine receptor genes Account for the proportion of variance in the larger range of action than the gene alone (Comings et al., 1997). Polymorphisms in the D1 receptor gene indicate severe alcohol May be more relevant to multidrug abusers than to addiction.   Dopaminergic genes, violence and schizophrenia / avoidance behavior. Another finding is "Pathology Complex personal disability, such as "active violence" and schizophrenia / avoidance behavior (SAB) Support the concept of polygenic inheritance in We have proposed DR in adolescent probands. Find a strong association between the D2 A1 allele and "pathological violence" and Similar association for 10 alleles of the min transporter gene (DAT1) Also found. For the DRD2A1 allele, a strong association with SAB was found, No association was found for the βH gene, but nevertheless the DAT1 gene Has a weak association with SAB (Blum et al., 1997).   Testing for DβH alleles tests the potential role of DβH in human behavioral disorders Can be the most accurate approach to This is DRD2TTaqIA1 with SAB vs. This is the first study to support a strong association between progeny and PV. These complex If the trait does not show a simple Mendelian pattern of inheritance, Don't expect a simple genetic answer triggered. Pathological violence of the dopamine gene The relationship to force is further described in specific Example 17.   Dopamine D2 receptor gene. Maintains in linkage imbalance with polymorphic markers Putative mutations located in the 3 'and 5' untranslated regions of the expressed gene are the DRD2 transcript and And / or may affect mRNA stability, and therefore may affect DRD2 receptor numbers based on: Affect: Rather than in exon point mutations, A stronger association with the marker; the “A1 marked” DRD2 allele Lack of reported mutations in exons (other than exon 8); Reduced DRD2 Bmax reported with the presence of the A1 marker in the presence (Noble et al., 1991). This helps explain one polymorphism, the lack of association with TaqID2. obtain. The lack of association with TaqI D2 indicates that TaqI A and B are in strong linkage disequilibrium with each other. However, the A1 3 'flanking marker shows less imbalance with TaqID and is a psychostimulatory selection. That weak association with alternatives therefore cannot be expected (Suarez et al., 1994). Consistent with population genetic analysis.   For more complex problems, explanations for failures in some studies can be found at Co It can be attributed to what mings (co-inventor) refers to as molecular heterosis. this is The subject's heterozygosity for the genetic polymorphism Significantly higher for quantitative trait variables (QTV) than homozygosity in all subjects (Positive hybrid stress) or low (negative hybrid stress) mean Occur.   Positron emission tomography (PET) studies show that alcohol has recovered from drug addiction Patients and cocaine abusers show reduced glucose metabolism in brain regions . In this study,¹⁸Use F-deoxyglucose for local glucose Xie, A1⁺Or A1^-Healthy non-alcoholic / non-drug abuse test using allele Was decided on. The mean value of relative glucose metabolism rate (GMR) is Includes nucleus accumbens, frontal and temporal gyrus, medial prefrontal lobe, occipital temporal, and orbital cortex A1 in many brain areas^-A1 than group⁺Was significantly lower. A1⁺ Reduced relative GMR in the group also indicated Broca field, anterior island, hippocampus, and It is also found in substantia nigra. However, some brain regions have A1⁺Group And showed increased relative GMR.   Suggests a role for loss of dopamine metabolism in the etiology of stress disorders There are several lines of evidence. Few dopa in the brain of A1 allele carriers Min D2 receptors are dopaminergic in these parts of the brain involved in reward It can be interpreted as a lower level of activity. A1 carrier finds A2 carrier happy It cannot be fully rewarded by stimulation. This is the desire for A1 career sustainability It can be interpreted as a solicitation or stimulus seeking behavior. Dopamine reduces stress or desire It is known that A1 carriers are trying to get temporary relief. And may be directed to other drugs or activities that release additional amounts of dopamine. A Alcohol, cocaine, marijuana, nicotine, and carbohydrates (chocolate All cause the release of dopamine in the brain, and Bring relief. These drugs can be used alone or to some extent They can be used interchangeably. Similarly, the DRD2 gene is (Comings et al., 1996b) and the work of other researchers (Noble et al., 1994; Lerman Et al., 1997).   Dopamine-β-hydroxylase. DβH is located at the sympathetic endings and The gene released into the circulation during the release of epinephrine and involved in this regulation is DβH It can be at a locus other than the gene itself. Therefore, the gene at the DβH locus Associations between markers and ADHD, CD, alcohol dependence, and other RDS-related behaviors The study was negative. On the other hand, serum DβH levels may vary depending on the range of environmental factors. Related studies using genetic markers for DβH, when made jointly with It may give a more accurate assessment of the role of the DβH gene in these disorders than in these disorders.   Taken together, these and other findings suggest that the DβH gene polymorphism Only in S behavior can it play a role, and DβH levels in the blood or its From the past literature on the product of activity (dopamine or norepinephrine), It is difficult to predict the actual result.   Dopamine-β-hydroxylase gene in drug abuse and other traits. DβH Inhibition of activity results in excessive production of dopamine, which can be hyperactive, aggressive, self-stimulating. Intense and associated with stereotypic behavior (Randrup and Scheel-Kruger, 1996) I do. It has been shown that DβH in aggression, ADHD and behavioral disorders (CD) in humans Suggest a possible role for For emotionally disturbed boys with low plasma DβH levels Reported increased frequency of CD diagnosis (0'Connell et al., 1992; Rogenes S. et al., 1984; Rogeness et al., 1986; Rogeness et al., 1988; Rogeness et al., 1987). Go Some studies have shown low DβH levels and the Eysenck Personality Questionnaire (Roy and And Brockington, 1987) and sensation seeking (Ballenger et al., 1). 983; Certain personal forms, such as extrovert scores in Umberkoman-Wita et al., 1981) Quality, while one study showed that between plasma DβH and sensory seeking scores Had a positive association (Folstein and Rutter, 1977).   Another aspect of the invention relates to related studies using the dopamine-β hydroxylase gene. And a first association between DβH dinucleotide repeat polymorphisms and drug abuse patterns (Comings et al., 1996a).   Dinucleotide repeat polymorphisms for DβH are lower or higher than 175 bp. It was found to have a bimodal allele distribution. Subjects should be homozygous Low (<174 bp) or high (<176 bp) or heterozygous The gene type was determined. Generally, patients with high bp homozygosity are found on ASI Higher number of previous drug treatments, longer cocaine use, more frequent Having IV injections of amphetamine, more frequent IV drug use. These subjects Paternal alcoholism is more frequent and was sexually abused in childhood He reported that he had a career. For parents with a high bp genotype, Self-Acceptanc e, Enlighted Second Nature, and lower score in Self-Directiveness Related to a.   Like the DRD2 A1 allele, the DβH B1 allele is a variable ADHD, paranoid obsession It is most associated with mania, mania, rebellious behavior, and sleep. The difference is the DRD2 A1 allele Offspring have a greater association with schizophrenia, sexuality, behavior, and stuttering variables, DβH B1 involves being more associated with learning, reading, and school problems. DβH Highly ranked in research, school activities such as reading, learning, and elementary school The trends in variables associated with dynamics are particularly pronounced when compared to DRD2 studies, Is Tends to be ranked lower. This may be related to the role of DβH in memory You.   Tourette syndrome (TS) may be one of the most complex recognizable forms of RDS . All actions associated with inhibition of DβH activity are common in patients with Tourette's syndrome (TS) (Comings and Comings, 1984; Comings and Comings, 1987b; Kne II and Comings, 1993; Comings, 1990), DβH Taq B polymorphism (d'Amano et al., 198). 9) and TS, behavioral disorders, attention deficit hyperactivity disorder (ADHD), autism, or related There may be an association between actions.   Elimination of the DAT1 gene in morbid obesity. The presence of the DRD2 A1 allele is only obesity But increasing the risk of other related addictive behaviors, and more than 25 BMI itself (macroselection [carbohydrate glut) or co-morbid SUD (Uncharacterized) is not a sufficient criterion for association with the DRD2 A1 allele. (Blum et al., 1996).   Studies in the area of morbid obesity that evaluate both the DRD2 A1 and DAT1 genes Shows only RD2A1 allele (p <0.0001) association with> 34% body fat DAT1 gene in women and not shown in men with more than 28% body fat Was. Maximum body weight occurs in individuals with the DRD2A1 / A1-DAT1-10 / 10 haplotype. This means that a much larger contribution is to the D2 receptor gene. Together, they suggest a contribution of both genes in morbid obesity.   Gene of cannabinoid receptor. The possibility of intravenous drug (IV) drug use remains. It can be affected by both transmissive and environmental factors. These genetic cultural diseases To study causal factors, 77 male non-Latin American white drug abusers and Seventy ethnically matched controls were tested. Apply intoxication severity index to patients The family environment size and early childhood experience survey questionnaire was applied to all probands, Dopaminergic gene, cannabinoid effector gene, and GABAergic gene The gene was genotyped. We have found that among subjects, higher morbidity The genotype of IV drug users is the CB1 (cannabinoid) receptor gene macromolecule Found to contain only low molecular weight alleles and low molecular weight alleles of GABRB3 gene Was. The CB1 gene is a 3 nucleotide repeat with at least 9 alleles and We note that the effect on phenotype is linear from the relative weight of the alleles. May not be predictable, but rather in their interaction with IV drug use. Was found to be complicated. Some environmental variables (from family environment scale Is associated with a predisposition to IV drug use after eliminating the variability associated with the genetic variable However, these environmental variables themselves are like genes that have not yet been identified. Can be under serious influence.   Electrophysiological abnormalities and drug use disorders (SUD): with dopamine D2 receptor Association with the cannabinoid receptor gene. Severe drug use disorders (SUD) DRD2A1 allele for "super control" and numerous literature controls (Blum et al., 1997; Hill et al., 1997). Trigger The decrease in P300 wavelength amplitude and latency of the continuous potential (ERP) is dependent on alcohol and It has been associated with drug dependence (Braverman, R et al., 1990). Significant extension of P300 latency Correlated with three risk factors: (1) parental SUD; (2) drug dependence (ie, coca (In dependence), and (3) carbohydrate gluttony. Reduced P300 amplitude is alcoholic And SUD, but not with the DRD2A1 allele.   In the present application, we have found that reduced frontal lobe P300 amplitude and cannabinoids Between homozygosity for the ≧ 5 repeat allele (CB1) of the receptor gene Provides evidence for a significant association. Alcohol or drug dependence 98 subjects and 69 controls from the ATU to determine if Were genotyped for the CB1 repeat allele. All subjects are non-Latin He was an American white man. ATU subjects were evaluated for toxicological indices, And evaluated using MAST-R. Drug and alcohol abuse / dependency Excluded from controls using only R. The result is a long-standing hallucinogen, Medication, heroin, opiates, amphetamine, cocaine, and barbitur With acid use, with IV drug use and drug overdose, and associated with drug abuse Legal issues such as drug retention, drug guilt, drug violations and resistance, assault, and public Many different types of drugs (cocaine, amphetamine, cannabis) with associated destruction) A significant association with homology for five repeat alleles with dependence was shown. versus In contrast, there was no significant association with variables associated with alcohol dependence. this is, Interviewed controls and / or assessment of severe alcoholism, especially complete RDS tables It can be attributed to the current system. However, these results indicate that cannabinoid receptors are rewarded Studies play a role in pathways and suggest that they regulate dopamine metabolism Matches.   We have found a significant relationship between brain electrical activity mapping (BEAM) abnormalities, and And DRD2 genotypes were identified. We have found that this is a genetic As an important confirmatory test for the diagnosis of induced predisposition, it has commercial value Think. This method uses a standard brain map (ie, Nicolett (^TM)) With human dopa Min receptor gene A1 allele and cannabinoid receptor gene (C It is suggested to include detection of NR1).   In addition, the linear trend of weight gain indicates that DRD2A2 genotype and Reveals significantly worsened effect of event-related potential in presence of 2A1 allele (P <0.0001). Duncan range test with or without DRD2A1 allele SUD showed significantly worse EP'S compared to DRD2A2 control . These results indicate non-behavioral pathophysiology, including brain function and potential addiction trends. Suggests a role for the DRD2A1 allele in various phenotypes.   Serotonin gene. Deficiency in serotonin metabolism and blood serotonin and Abnormalities in both levels and tryptophan levels are associated with many psychiatric disorders. Have been reported. Tryptophan 2,3-dioxygenase (TD02) It is a rate limiting enzyme for breaking down tophan into N-formylkenurenin. Departure The authors point out that genetic alterations are associated with TS or any of its associated serotonin HTRIA We considered whether to determine whether the coexisting behavior was associated with the phenotypic expression. General Presence (shorter and longer alleles) and ADHD, CD, And religious behavior disorder (ODD), tics, sexual behavior, and other behavioral There was a significant relationship with a. The contribution to these scores is modest and ranges from 2 to Occupies only 4%. The effects of the HTR1A and DRD2 genes are additive and Accounted for 5.1-5.4% variation in ADHD, CD, and ODD scores. These results Of altered genes and environmental factors affecting serotonin and dopamine metabolism Consistent with the assumption that these are polygenic disorders, partially due to opportunity convergence You. Repeat sequences themselves are important functional allele morphological alterations in polygenic inheritance. May play a role in the production of varieties.   T / C polymorphisms in the 5HT-2 receptor gene also indicate that Axis II personality disorder Interview and Additive Severity Index (ASI) and Buss-Durkey Rebellion Scale (BHDS) Used to test for possible associations. In patient samples, 22 genotypes It was associated with a diagnosis of the borderline of personality disorder (p <0.05) and depression (p <0.05). To ASI In this marker, the amount of drug spent (p <0.05) and rape history (p <0.05) p <0.05) and shoplifting / public property damage (p <0.05). At BHDS In male controls, 22 genotypes were assaulted (p <0.05) and indirect It was associated on a semi-scale with increasing scores in rebellion (p <0.05). Female control In 5HT-2R genes, indirect rebellion (p <0.01), rejection (p <0.05), Leaf rebellion (p <0.05) and guilt (p <0.05), and overall rebellion score (P <0.01), but in the opposite direction (eg, 11 genotypes Associated with higher ratings in all scores). This is a genotype-related sex change Indicates a complex gene that can interact with sex steroids.   Estrogen receptor, aromatase locus, and arginine vasopre Syngenes, as well as behavioral disorders. Estrogen receptor knockout mouse Exhibit aggressive behavior (Ogawa et al., 1996), indicating that Reverse studies (del Senno et al., 1992) may also be associated with behavioral disorders. Two other associations The genes include the aromatase gene (CYP 19) locus (Polymeropoulos et al., 1991) and The gene was derived from the arginine vasopressin (AVP) gene (Summar, 1992).   Nicotinergic receptor gene. Nicotinic receptors in the prefrontal cortex Puter is involved in the delayed response task, while muscarinic Agonist receptors are involved by general working memory (Granon et al., 1995). Many Studies have shown an intimate interaction between nicotine and dopamine. Other addictive drugs Like the nicotine, nicotine is administered in the limbic and nucleus accumbens nerves (DiChiara and And Imperato, 1988; Corrigall et al., 1994; Pontiefi et al., 1996); Robust self administration (Corrigall and Coen, 1989; Corrigall And Coen, 1991) produce an increase in the release of dopamine. But, Tolerance develops rapidly with repeated administration (Lapin et al., 1989). Nicotine Dopamine uptake differently than most dopamine uptake inhibitors But only 50% (Irenwasser et al., 1991). Dopamine uptake Inhibitors and nicotine receptor agonists and antagonists Studies show that the effect on dopamine uptake is nicotinic acetylcholine receptor Suggests that it is mediated through the interceptor (Orenwasser et al., 1991).   Gene for nitric oxide synthase (NOS) in neurons. Nitric oxide synthase gene Has recently been associated with aggressive behavior in mice. ob / ob mouse Study increases nitric oxide synthase (NOS) levels compared to non-ob / ob littermates Indicates that Studies of NOS knockout mice have shown that aggressive and sexual The important role of nitric oxide in Ob / ob mice also have Increased levels of norepinephrine in the brain and hypothalamus, arcuate Showing significantly reduced levels of dopamine in the funnel (arcuate-infundibulum) (Oltman, 1983).   Dinucleotide repeat polymorphism of the nitric oxide synthase gene (nNOS1a) in neurons Sex relationships were investigated. Measures of rebellion, diagnostic features, and personality traits were Ten-American white drug abusers and 68 age- and ethnic-matched Evaluated in Troll. AXIS-11 personality disorder structured interview Review, addiction severity index (ASI), and Cloniger temperament and personality inventory (TCI). And evaluated. The distribution of patient and control alleles Slightly different from patients homozygous for the gene (p = 0.056). AXIS-II Patients homozygous for high molecular weight alleles in interviews (≥201) Is more frequent in schizophrenic personality disorder (p <0.05) and borderline personality disorder (p <0.05) The diagnostic criteria were reached. In the ASI, this genotype committed violence in the last 30 days (p <0.0005), history of forgery (p <0.05), history of theft (p <0.0.05), Alco in the past 30 days Tool use (p <0.005), years of inhalation use (p <0.0075), number of drug detoxifications (p <0.05) 5) Experienced problems with alcohol (p <0.005) and drugs (p <0.005) The number of days in the past month was associated with an increased score. This genotype is Also, fewer friends (p <0.04), fewer friendships with friends you have (P <0.0005) and was associated with a higher number of marriages (p <0.05). To TCI In this genotype, increased impulse (p <0.01), as well as attachment (p <0.05) Dependence (p <0.02), reward dependence (p <0.05), purpose (p <0.01), self-directivity (Se lf-Directiveness) (p <0.05), empathy (p <0.05), benefit (p <0.02), simple sincerity It was associated with a reduced score in fruit (p <0.02), and cooperation (p <0.05).   Monoamine oxidase gene transfer (MAO). MAO is a neurotransmitter at the brain synapse. It is one of the main enzymes responsible for the degradation of chemicals. Significant in mood and other behaviors The improvement results from the administration of a medicament that inhibits MAO activity. Many studies have low M AO levels and alcoholism (Wiberg et al., 1977; Gottfries et al., 1975; Devor et al., 1994) ; 09); schizophrenia (Wyatt et al., 1979); depression (Sherif et al., 1991; Pandy et al., 1992). Manic-depressive disorder (Pandey et al., 1980); Suicide (Gottfries et al., 1975; Sherif et al., 1991) Buchsbaum et al., 1976; Buchsbaum et al., 1977; Meltzer and Arora 1986); Also known as ADHD (Skekim et al., 1982); and preferring danger, stimulating, and Externalizes personality traits (Vonknorring et al., 1991; Buchsbaum et al., 1976; Schooler et al. , 1978; Shekim et al., 1989; Vonknorring et al., 1984). Sa Still other studies failed to find an association with one or more of these traits (Mann and Stanley 1984; Propping et al., 1981; Tabakoff et al., 1988). Both enzymes level (Wiberg et al., 1977; Gottfries et al., 1975; Devor et al., 1994; Vonknorring et al., 1991) And previous studies using genetic modifications (Vanyukov et al., 1993) Suggests a role for the MAOA gene in   In addition to dopaminergic systems and cannabinoid receptors, Oxidase (MAO) also implicated as playing a key role in RDS Have been. The present invention also relates to monoamine oxidase residues in Tourette's syndrome. A first variant of a gene variant is provided. X linkage MAOA or MAOB gene Gene deficiency in women may explain that men have more ADHD, TS, and related disorders You. Alleles of three repetitive polymorphisms (351 Ts patients, relatives, and control (2 MAOA and 1 MAOB gene in all). Each subject has a behavior Enables the evaluation of 23 different quantitative traits for problems, learning problems, and school problems I answered all the structured questionnaires. ADHD, stuttering, mania, depression, behavior, and learning More associated with MAO VNTR and MAOB polymorphisms, associated with higher scores for the problem Long base pair (bp) alleles, as well as shorter bp alleles of the MAO CA-1 polymorphism There was a significant tendency for the offspring. The most significant results were ADHD (p = 0.005), major depression CA-1 repeats of the MAOA gene for disease (p = 0.005), and stuttering (p = 0.007) there were. The regression coefficients of the seven behaviors were significant at <0.01, but the sex linkage MAOA R in denko^TwoOr the percentage of variants contributes to the range of behavior, and the degree of Explain that S, ADHD, or CD are more common in men. The result is the TS spectrum The genetic polymorphism mechanism of the disorder and the minisatellites themselves are involved in gene regulation Consistent with the hypothesis that it could play a role.   OB, human chromosome 2, unbound protein-2, and APO-D genes in obesity . Recruitment studies show higher degrees of genetic burden for obesity in women than in men Genetic factors are more involved in obesity in young people than in ages above 50 (Where the incidence of obesity increases in a large proportion of the population, and Wearing habits like sitting lifestyles can be more important) Accompanied (Stunkard et al., 1986).   An important protein product involved in obesity is the serum protein leptin. So Synthesis is regulated by the OB gene and plays a key role in controlling body fat (Maffei et al., 1995). Leptin levels in humans It has been found to be highly associated with excess body fat (Considine et al., 1996) . Microsatellite polymorphism D2S1788 was found to map to chromosome 22p21. However, this is evidence of linkage by rod scores at serum leptin levels. (Comuzzie et al., 1997). This locus is associated with serum leptin levels. And some potential candidate genes for obesity (groups). Lucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC) )) (Comuzzie, 1997). Potential mechanisms associated with the POMC gene Are involved in the adrenal cortex, which acts on the adrenal cortex, which leads to glucocorticoid production. It is a precursor of the intense hormone (ACTH). However, the POMC gene is also a precursor It is possible to speculate that the body acts on opioid peptides.   Mitochondria called uncoupling protein (UCP1) Protein plays an important role in fever and calories burned (Nicholls And Locke, 1984). This pathway regulates body temperature, body composition, and glucose Related to Xie (Himms-Hagen, 1990). However, UCP1-containing brown adipose tissue, Not be involved in weight control in human survival in a thermalneutral environment It is. UCP-2 has a 59% amino identity with UCP-1 and has been shown to reduce diabetes and obesity (Fleury et al., REFERENCE). UCP-2 is expressed in yeast In this case, it has a greater effect on mitochondrial membrane potential than UCP-1. U CP-2 is widely found in adult human tissues, including macrophage-rich tissues Expressed and in white fat in response to fat intake Up-regulated.   The present invention is directed to all of these obesity genes, which represent a number of different physiological mechanisms. With polygene analysis). These differences are additive rather than synergistic And may lead to more accurate DNA-based pre-diagnostic tests. One sample And combining the DRD2, OB, chromosome 2, UCP-2, and APO-D genes, It is a preferred embodiment over any gene alone. Further, the present invention relates to BMI (this This is not the best obesity decision), but rather the percentage of body fat (for women Up to 34% and up to 28% for men) decide. Multi-gene approach in SUD   One of testing alleles of many different genes in the same set of subjects One unique advantage is that the relative effects of each gene are compared for different quantitative variables. Is to get. In addition, genotyping is important if the effects of the gene are separated from environmental causes. And sophistication for the analysis of environmental effects in that they can be analyzed Add degrees.   Moos 'Family Environment (Moos' Family Environment) 1 Scale (FES) on a scale of 10 for childhood and It was used as an indicator of the environment of the subject's family during puberty. The data is SPSS (SPSS, Inc.) Correlations and Partial   Analyzed using Correlations software.   Analysis of each drug variable was performed using marker loci at seven loci as predictive indicators. We started with stepwise regression using the gene form. Variable production with p value less than 0.05 required Entered in raw equation. After each regression, the variables associated with the smallest predictor gene were removed. Different The results showing the correlation coefficients for different genes and environmental factors are shown in Table 1. You. Step 4. The fourth step is to identify one or more polymorphisms associated with each gene. is there. These are single strand base pair restriction fragment length polymorphisms (RFLP), or Dinucleotides, trinucleotides or other repetitive polymorphisms (eg, variable Dem repeats) or any other marker at the locus. Such polymorphisms Sex and detection methods identify candidate genes in addition to the polymorphisms disclosed herein. To do so, previously published or unpublished research, as described above, It can be easily used in the final writing. Alternatively, one gene is the target If suspected to contribute to the offspring trait, polymorphism is currently not available for use in MAA technology. Although not available, after reviewing the literature and the gene database, the gene (which , Which can be used in MAA technology) to determine polymorphisms. Essays may be conducted. Such assays are in addition to the techniques described herein. And are commonly used and described in the literature. Genomic DNA, cD Gene screening for accurate detection of mutations in NA or RNA samples The method used can be used depending on the particular situation.   The present invention uses the detection, diagnosis, prognosis and treatment of RDS disease, and MAA technology. The detection, diagnosis and prognosis of the polygenic trait used. Allele marker (Additionally or decreasingly polymorphic genetic forms in the form of nucleic acid sequences isolated from an individual New markers for use in MAA assays) And a method of detecting. These markers should be assayed It is an indicator of a contagious trait and is a potential diagnostic for individuals with a particular trait. is there.   One skilled in the art will appreciate the nucleic acid sequences disclosed herein, and public databases ( Public (as found in the National Center for Biotechnology Information) That sequences available from the published scientific literature can be used in MAA technology Understands, and therefore detects, diagnoses, prognoses, and treats or RDS or other Find diverse utility in polygenic traits in Such within the scope of the present invention Examples of applications are markers for one or more polygenic traits using specific primers Hybridization with oligonucleotide or nucleic acid probes Detection of polygenic trait markers, such as by By integration, and by expression of RNA from a vector.   To test for multiple genes in behavioral disorders and other polygenic traits Is practical and does not require new technology. Polymorphisms and variants Are two types, 1) restriction fragment length polymorphism (RFL P), and 2) short tandem repeat polymorphisms (STR) [typically di and tri Nucleotide repeats]. Those for large scale testing these The method is different for each type. RFLP. Applied Biosystems (Perkin-Elmer   Corporation, a division of the Corporation)^TMPair of RFLP-type remains based on Developed new technologies and equipment to enable rapid testing for gene polymorphisms . This device (Applied Biosystems Prism 7200) The Sequence Detection System (TaqMan) Enables multigene testing. This approach uses restriction endonuclease polymorphisms Use standard primers to electrophorese sections of DNA that contain To use. A unique aspect of this technology is that two short oligomers are then degraded, One matches one of the alleles and the other matches one other allele A fluorescent dye is attached to one end of each, and a quenching dye is attached to the other end. Is done. If the match is perfect, the DNA polymerase hybridized When it reaches the ligomer, it becomes a nucleotide as the polymerase passes. Decomposed. This releases the quencher, where the dye fluoresces maximally. To color. However, if the oligomers do not match, instead of nuclease degradation , The oligomer leaves the site and quenching persists. Plate double wave It allows discrimination between genotypes of long readings 11, 12, 22. 96 samples The overall process of reading the results for is less than 15 minutes, and the results are Sent to computer for analysis and storage. This technology (PCR^TMreaction Assisted by a computerized workstation to set up Helped) allows hundreds of different RFVPs to be tested in one day. STR. The same computerized workstation used above is the STR PCR for^TMUsed to set up the reaction. The difference is the STR Is that the primers themselves are labeled with different fluorescent dyes. Only 2bp The accuracy required to identify alleles that differ by Applied Biosystems 373 DNA sequencer (this is Make the second label dyeable with a second dye). Each has a different wavelength laser Detected by scanning. For example, one PCR^TMThe primer is a phosphor HEX Amidite (Applied Biosystems, Foster City) , CA) or other fluorochrome dyes. Then, 2 μl of a 10-fold dilution was performed. PCR^TMThe product is treated with 2.5 μl deionized formamide and 0.5 μl RO X500 standard, denatured at 92 ° C for 2 minutes, and AB3737 DNA Load on a 6% denaturing polyacrylamide gel in sequencer. Get The sample is electrophoresed at a constant 25 W for 5 hours. The gel is laser scanned and each Analyzed using an internal ROX500 standard present in the Peak is base pair length Genotyper (v version 1.1).   Historically, a number of different methods have been used to detect point mutations ( Denaturing gradient gel electrophoresis ("DGGE") restriction enzyme polymorphism analysis, chemical and enzyme Cutting method, and other methods). A more general procedure for current use is , PCR^TMSequencing of the target region amplified by (see below) And single-strand conformation polymorphism analysis ("SSCP").   Another method for screening for point mutations is RNA / DNA and RNA. / RNase cleavage of base pair mismatches in RNA heteroduplexes. Book As used in the invention, the term “mismatch” refers to double-stranded RNA / RNA, R One or more pairs of NA / DNA or DNA / DNA molecules Or mispaired nucleotides. So this definition is Includes deletion mutations and mismatches due to single-stranded and multiple base point mutations.   US Patent No. 4,946,773 describes a RAase A mismatch cleavage assay. (Annealing single-stranded DNA or RNA test sample against RNA probe And subsequent treatment of the nucleic acid duplex with RNase A) It has been described. After the RNase cleavage reaction, RAase is inactivated by proteolysis. Activated and extracted with organic solvent, and the cleavage product is heated Denatured and analyzed by electrophoresis on a denaturing polyacrylamide gel. For mismatch detection, the single-stranded product of RNase A treatment (depending on size) Electrophoretically separated) is compared to a similarly treated control duplex. You. Contains small fragments (cleavage products) not found in the control duplex Samples are scored as positive.   Currently available RAase mismatch cleavage assays (US Pat. No. 4,946,946) No. 773), which includes assays for radiolabeled RNA probes. Including use. Myers and Manian in U.S. Pat. No. 4,946,773. tis describes the detection of base pair mismatches using RNaseA. other Researchers in an E. coli mismatch assay. RNase, an E. coli enzyme Describes the use of I. It has broader cleavage specificity than RNaseA The component reduces the spread of non-specific cleavage and the cleavage of mismatches If it can be found to increase the frequency of Is an enzyme that is desired to be used in the detection of For mismatch detection The use of RNase I is described in the literature from Promega Biotech. You. Promega claims that RNase I (assuming that the enzyme levels are high enough) Indicate that they cut three of the four known mismatches in these references. Kits are commercially available.   RNase protection assay detects the end of specific mRNA targets in solution First used to detect and map. Assay for in vitro transcription Thus, a highly specific active radiolabeled RNA probe complementary to the mRNA of interest Can be easily produced. Originally for in vitro transcription Template is a recombinant plasmid containing the bacteriophage promoter Met. Probes can hybridize to these complementary targets Mixed with the total cellular RNA sample, and then the mixture is RNase treatment was performed so as to decompose the unduplicated probe. Also, originally intended As used, the RNase used is specific for single-stranded RNA. for that reason In addition, the hybridized double-stranded probe is protected from degradation. Inactivation and After removal of the RNase and RNase, the protected probe (which is Is proportionally recovered) and analyzed on a polyacrylamide gel. You.   RNase protection assay matched for single base mutation detection Was. In this type of RNaseA mismatch cleavage assay, In vitro transcribed radiolabeled RNA probe is complementary to the test sample To the target region. RNA targets (endogenous mRNA) Usually, the test target is DNA (genomic DNA or plasmid). By cloning or PCR^TMDNA amplified by). single Probes that have hybridized nucleotide (or larger) sequence differences Watson-click at that location ("mismatch") if it occurs between Disruptions that occur in hydrogen bonds can be recognized and, in some cases, single-strand-specific Cleavage by bonuclease. To date, RNase A has been RNase I has been used almost exclusively for cutting It is also shown to be useful for latch cutting. Detection of single base mismatch Recent Descriptions Using MutS Protein and Other DNA Repair Enzymes for Export There is. Additional methods for the detection of nucleic acids and mutations are described herein. . Nucleic Acids As described herein, aspects of the present disclosure are directed to allelic variants. Markers of transgenic traits (ADHD, rebellious behavioral disorders, behavioral disorders, learning disabilities, al Including markers such as Cole, Cholesterol, and LDL), 29 Is a previously known gene.   In one embodiment, the nucleic acid sequences disclosed herein are hybridized Find utility as a sation probe or amplification primer. these The nucleic acids can be used, for example, in the diagnostic evaluation of tissue samples, or Used to clone the long cDNA or its corresponding genomic clone. Can be In certain implementations, these probes and primers Consists of nucleotide fragments. Such fragments may be RNA or To provide specific hybridization to a DNA tissue sample, It should be a reasonable length. The sequence is typically 10-20 nucleotides May be longer nucleotides. Longer sequences (eg, 40, 50, 1, 00, 500 and even up to full length) are preferred for certain embodiments.   Any gene (which may be used in the diagnostic or treatment methods disclosed herein) About 10, 15, 17, 20, 30, 4 from a sequence selected from (can be used) 0, 50, 60, 75 or 100 or 500 nucleotides A nucleic acid molecule having a switch is contemplated. Complementary to the sequence described above and high Molecules that bind to these sequences under increasingly stringent conditions are also possible . These probes can be used in a variety of hybridization embodiments (eg, Southern). And Northern blotting). In some cases, multigene Without compromising their ability to effectively diagnose sexual traits, multiple target It is possible that a probe could be used to hybridize to a row .   Various probes and primers are disclosed nucleotide sequences, or markers. Kerr (which may be a gene disclosed herein or a 29 described herein) Surrounding the useful sequence (to the latter gene added to the set of genes) It can be designed around polymorphisms. Other genes are for testing different polygenic traits Can be used to create a new set of Use of other genes or, preferably, gene polymorphisms is included as part of the invention It is intended to be. Primers can be of any length, but are typically 1 It is 0-20 bases long. Assign a numerical value to the sequence (eg, the first residue is 1 , The second residue is 2, etc.) to define all primers by Can be provided:                 From n to n + y   Where n is an integer from 1 to the last number of the sequence, and y is the primer Length-1 (9 to 19), where n + y does not exceed the last number in the array. Thus, for the 10-mer, the probe is base 1-10, base 2-11, base 3-3 12 ... corresponds to For the 15-mer, the probe is base 1 to 15, bases 2-16, bases 3-17 ... and so on. About 20 mer The probe may continue at bases 1-20, bases 2-21, bases 3-22 ... and so on. , Corresponding to.   In certain embodiments, the multiplex probes hybridize to a single sample. It is intended that it can be used for the purpose of zonation. 14 nucleotides long and 10 The use of hybridization probes between 0 nucleotides in length is stable and And the formation of double-stranded molecules that are both selective and selective. Strikes longer than 20 bases Molecules with sequences that are complementary across the retches are important for hybrid stability and stability. Quality and specific hybrid molecule obtained by Generally preferred for improving the degree. One skilled in the art will recognize 20-30 nucleotides or Design nucleic acid molecules with longer stretches of nucleotides, if desired Like that. Such fragments may be, for example, by chemical means, or By introducing the selected sequence into a recombinant vector for recombinant production, It can be easily prepared by directly synthesizing the fragment.   Accordingly, the nucleotide sequences of the present invention may be used as complementary strains for genes or RNA. To form double-stranded molecules selectively with DNA or RNA from tissue. These capabilities can be used to provide primers for amplification. Feeling Depending on the application to be determined, one skilled in the art will vary the degree of selectivity of the probe for the target sequence. It is important to change the hybridization conditions to achieve Hope.   For applications requiring a high degree of selectivity, those skilled in the art It is desirable to use relatively stringent conditions for this. For example, those skilled in the art Are relatively low salt and / or high temperature conditions (e.g., at a temperature of about At about 0.02M to about 0.10M NaCl). Such highly stringent conditions are associated with the probe and template or standard. Little, if any, mismatches with the target chain, and For isolating a specific gene or detecting a specific mRNA transcript Especially suitable for: Conditions are more stringent by adding increasing amounts of formamide. It is thought that the event can be given.   For certain applications, such as amino acid substitution by site-directed mutagenesis, It will be appreciated that low stringency conditions are desired. Under these conditions, Even if the probe and target strand sequences are not perfectly complementary, Even if there is a mismatch, hybridization can occur. condition is, Recessive stringing by increasing salt concentration and increasing temperature Event conditions. For example, moderately stringent conditions are at about 37 ° C. May be provided by about 0.1 M to about 0.25 M NaCl at a temperature of However, low stringency conditions may range from about 20 ° C. to about 55 ° C., It may be provided by 0.15M to about 0.9M salt. Therefore, the hybridization The operation conditions are easily manipulated and, therefore, generally the choice depends on the desired result. This is the method.   In another embodiment, the hybridization is performed with 50 mM Tris-H. Cl (pH 8.3), 75 mM KCl, 3 mM MgCl_Two, 10 mM dithio Threitol may be achieved under conditions at a temperature between about 20C and about 37C. Used Another hybridization condition that may be used is about 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 μM MgCl_TwoAbout 40 ° C. to about 72 ° C. Temperatures in the range between may be included.   In certain embodiments, a suitable method for determining hybridization is provided. The use of a nucleic acid sequence of the invention in combination with a step (eg, a label) is advantageous. is there. A wide variety of suitable indicator means can be detected, such as phosphors, Radiolabel, enzymatic ligand or other ligand (eg avidin / biotin) And are known in the art. In a preferred embodiment, those skilled in the art Fluorescent labels or enzyme tags instead of active or other environmentally undesirable reagents (E.g., urease, alkaline phosphatase or peroxidase) May be desired. In the case of an enzyme tag, a colorimetric indicator substrate is known. this Identifies specific hybridization with a sample containing complementary nucleic acids In order to provide a detection means that becomes visible to the human eye or spectroscopy Can be used.   Generally, the hybridization probes described herein will have the corresponding For the detection of gene expression and in embodiments using a solid layer, the solution As a hybridization reagent and PCR^TMYes as both as a reagent It is for. In embodiments comprising a solid phase, the test DNA (or RNA) is adsorbed Or otherwise applied to a selected matrix or surface. Next In this, the immobilized single-stranded nucleic acid is combined with the selected probe under desired conditions. Receive hybridization. The selection criteria depend on the specific environment required (eg, , G + C content, target nucleic acid type, nucleic acid source, hybridization probe Depends on specific criteria based on the size). Non-specific binding probe After washing the hybridized surface to remove the Solution is detected or even quantified by labeling means.   Amplification and PCR^TM   Nucleic acids used as templates for amplification are produced using standard methodology (Sam). Brook et al., 1989), from cells contained in a biological sample. Separated. The nucleic acid can be genomic DNA or fractionated or cellular total RNA . If RNA is used, it may be desirable to convert the RNA to complementary DNA . In one embodiment, the RNA is total cellular RNA and for amplification Used directly as a template.   Primer pairs (which selectively bind to nucleic acids corresponding to genes of a polygenic trait) Hybridizing) but under conditions that permit selective hybridization. Contacting the isolated nucleic acid. The term “primer” as defined herein Can prime the synthesis of nascent nucleic acids in a template-dependent process Includes any nucleic acid. Typically, primers are 10 to 20 or Is a 30 base pair long oligonucleotide, but longer sequences may be used. Primers can be provided in single-stranded or double-stranded form, although single-stranded forms are preferred. No.   Once hybridized, the nucleic acid: primer complex is template-dependent Contacted with one or more enzymes that promote nucleic acid synthesis. Also called a "cycle" Multiple rounds of amplification are performed until a sufficient amount of amplification product is produced.   Next, the amplification product is detected. In certain embodiments, detection is by visual means. Can be implemented. Alternatively, detection can be by chemiluminescence, incorporated radiolabel or Via radioactive scintigraphy of fluorescent labels or by electrical or thermal shock Through a system that uses signals (Affymax technology) Indirect identification of the product.   Many template-dependent processes exist in the provided template samples. It can be used to amplify existing marker sequences. The most well-known amplification method One method is the polymerase chain reaction (PCR).^TMCalled). This is rice National Patent Nos. 4,683,195, 4,683,202 and 4,80 No. 0,159, each of which is incorporated herein by reference in its entirety. Used).   Briefly, PCR^TMThe two primer sequences are opposite to the marker sequence Is prepared to be complementary to the region on the complementary strand of Excess deoxynucleotide Otide triphosphate is a DNA polymerase (eg, Taq polymerase) ) Is added to the reaction mixture. If the marker sequence is present in the sample, The primer binds to the marker and the polymerase Thus, a primer is created to be stretched along the marker sequence. reaction Stretched by raising and lowering the temperature of the mixture The dissociated primer dissociates from the marker to form a reaction product. Excess primer Binds to the marker and reaction product, and the process is repeated.   Reverse transcriptase PCR^TMAn amplification procedure is used to quantify the amount of mRNA amplified. Can be applied. Methods for reverse transcription of RNA into cDNA are well known, and Look, et al. (1989). An alternative method for reverse transcription is thermal Use a stable, RNA-dependent DNA polymerase. These methods are described in 1990. WO 90/07641 filed on December 21, 2000, which is hereby incorporated by reference. Cited in the book). Polymerase chain reaction methodology Well known in the field.   Another method for amplification is the ligase chain reaction (“LCR”), No. 320380, which is hereby incorporated by reference in its entirety. Is shown. In LCR, two complementary probe pairs are prepared and the target In the presence of a row, each pair binds to the opposing complementary strand of the target such that they make contact I do. In the presence of ligase, the two probe pairs form a single unit Connect to PCR by temperature cycling^TMAs well as linked and linked The unit dissociates from the target and then “target sequence” for ligation of excess probe pairs. Serve as. U.S. Pat. No. 4,883,750 discloses a probe that binds to a target sequence. A method analogous to LCR for bu pairs is described.   PCT Application No. PCT / US87 / 00880, which is incorporated herein by reference. Qβ replicase, which is incorporated herein by reference, is also a further alternative of the present invention. It can be used as an amplification method. In this method, the RNA replication sequence (which is (With a region complementary to the region of the target) Is added to the The polymerase copies the replicated sequence (which can then be detected) I do.   Isothermal amplification methods (restriction endonucleases and ligases are used to target The nucleotide 5 '[α-thio] -triphosphate on one strand of the restriction site). (Used to achieve width) are also useful in amplifying nucleic acid molecules of the invention. .   Strand displacement amplification (SDA) is an isothermal amplification of nucleic acids (which involves multiple rounds of strand displacement and And other methods for performing synthesis (ie, nick translation). Is the way. Another method, called the replication chain reaction (PCR), involves the (There are two 4 bases), which covers the entire region targeted for amplification. Just involves annealing some of the probes. The other two bases are It can be added as a biotinylated derivative for easy detection. A similar approach Used in SDA. Target-specific sequences can also be used in cyclic probe reactions. (CPR). In CPR, 3 'of non-specific DNA And the 5 'sequence and a probe having an intermediate sequence of the specific RNA are included in the sample. Hybridizes to DNA present in Reaction during hybridization Is the probe treated with RNaseH and identified as apparently product. The product is released after degradation. The original template is different from another cyclic probe Annealed and the reaction is repeated.   GB Application No. 2202328 and PCT Application No. PCT / US89 / 01025, each of which is incorporated herein by reference in its entirety. Still another amplification method described in can be used according to the present invention. In previous application The "modified" primers^TMLike, template and enzyme dependent Used in existential synthesis. The primer can be a capture moiety (eg, bubiotin) And / or can be modified by labeling with a detection moiety (eg, an enzyme) . In later applications, excess labeled probe is added into the sample. Target sequence In the presence of the probe binds and is cleaved catalytically. After cleavage, the target sequence Is released intact and bound by excess probe. Cleavage of the labeled probe Signal the presence of the target sequence.   Other nucleic acid amplification procedures include nucleic acid sequence-based amplification (NASBA) and 3SR (G ingeras et al., PCT Application No. WO 88/10315, which is incorporated by reference. (Incorporated herein), including a transcription-based amplification system (TAS). . In NASBA, nucleic acids are prepared using standard phenol / chloroform extraction, Lysis buffer and mini for heat denaturation of bed samples, isolation of DNA and RNA Amplify by spin column preparation or RNA guanidine chloride extraction Prepared for These amplification techniques use primers with target-specific sequences Annealing. After polymerization, the DNA / RNA hybrid Although degraded by aseH, the double-stranded DNA molecule is heat denatured again. In any case , The single-stranded DNA is added to the second target-specific primer by polymerization. To make it sufficiently double-stranded. The double-stranded DNA molecule is then T7 or S Multiple transcribed by an RNA polymerase such as P6. Isothermal cyclic anti In response, the RNA is reverse transcribed into single-stranded DNA. This is then double-stranded DNA And then again with an RNA polymerase such as T7 or SP6 Will be copied. The resulting product (whether truncated or complete) ) Indicates the target-specific sequence.   Davey et al., EPA 329822, which is incorporated by reference in its entirety. Are single-stranded RNA ("ssRNA"), ssDNA, and double-stranded DNA Nucleic acid amplification process, including the cyclic synthesis of (dsDNA) Which may be used in accordance with the disclosure). ssRNA is the primary primer Template for oligonucleotides, which is a reverse transcriptase (RNA-dependent DNA polymerase). RNA is then ribonucleic ASE H (RNaseH, either DNA or RNA and RNA in duplex) DNA: RNA generated by the action of the characteristic RNase) You. The resulting ssDNA is a template for the second primer, which is again RNA polymerase promoter due to its homology to the template 5 '(exemplified by T7 RNA polymerase). Then, Primers are double-stranded DNA ("dsDNA") molecules (the original Has a sequence identical to the sequence of the RNA, and further comprises a promoter sequence at one end DNA polymerase (E. coli DNA polymerase) Stretched by "Klenow" fragment of I) It is. This promoter sequence can be used by a suitable RNA polymerase. Make many RNA copies of DNA. These copies are then Cycle readings can be re-entered for rapid amplification. Proper selection of enzymes Thus, this amplification is done isothermally without the addition of enzyme in each cycle. This Due to the cyclical nature of the process, the starting sequence may be in the form of either DNA or RNA May be selected to exist.   Miller et al., PCT Application No. WO 89/06700 (which is incorporated by reference in its entirety). (Incorporated by reference) is the target single strand following transcription of many RNA copies of the sequence. Hybridization of promoter / primer sequences to DNA ("ssDNA") A nucleic acid sequence amplification scheme based on a solution is disclosed. This scheme is cyclic Not (ie, the new template is not produced from the resulting RNA transcript). No). Other amplification methods include “RACE” and “One-sided PCR ™” (Fromhm an, 1990, which is incorporated herein by reference).   The resulting "dioligonucleotide" sequence, thereby Two (or more) oligonucleotides in the presence of a nucleic acid that amplify otide Methods based on ligation of tides can also be used in the amplification step of the present invention. Any amplification Of determining the template and whether a particular amplification occurs according to It may be desirable to separate amplification products from excess primers for targeting. One In one embodiment, the amplification product is prepared by standard methods (Sambrook et al., (198). 9)) using agarose, agarose acrylamide or polyacrylic Separated by amide gel electrophoresis.   Alternatively, chromatography techniques can be used to make the separation effective . There are many types of chromatography that can be used in the present invention: adsorption, partitioning, Ion exchange and molecular sieving, and columns, paper, thin layers and gas chromatographs Many expertise using chromatography, including toography.   Amplification products must be visualized to confirm amplification of marker sequence . One representative visualization method is gel staining with ethidium bromide and UV light Including visualization below. Alternatively, the amplification product is a radioactively or fluorescently labeled nucleic acid. If fully labeled with otide, then the amplification product can be separated by X-ray filtration following separation. Exposure to LUM or visualization under the appropriate stimulus spectrum.   In one embodiment, visualization is achieved indirectly. Subsequent to amplification product separation Then, the labeled nucleic acid probe is contacted with the amplification marker sequence. preferable The probe is bound to a chromophore but can be radiolabeled. In another embodiment The probe is bound to a binding partner (eg, antibody or biotin) and The other member of the binding pair is retained on the detection moiety.   In one embodiment, the detection is performed with Southern blots and labeled probes. By hybridization. The techniques involved in Southern blots are well known to those of skill in the art. Yes, and is found in many standard books on molecular protocols. Sambrook See k et al. (1989). Briefly, amplification products are analyzed by gel electrophoresis. Separated. The gel is then contacted with a membrane (eg, cellulose), which Allows movement and non-covalent bonding. Subsequently, the membrane is a chromophore-bound probe (this Allows to hybridize with the target amplification product) Is done. Detection can be by exposure of the membrane to X-ray film or by an ion excitation detection device. You.   One such example is described in US Pat. No. 5,279,721, which is incorporated herein by reference. For automated electrophoresis and transfer of nucleic acids. An apparatus and method are disclosed. The instrument is compatible with electrophoresis and And ideally matches the method implemented according to the invention.   Detect genetic markers for one or more polygenic traits in a biological sample All the necessary materials and reagents needed for can be assembled into a kit. Generally, this will include the primers that have been preselected for the specific marker. Ma For nucleic acids to be amplified, including various polymerases (RT, Taq, etc.) Appropriate enzymes, deoxynucleotides to provide the necessary reaction mixture for amplification Tide and buffers may be included.   Such kits, in appropriate means, provide for each individual reagent and enzyme. , As well as a separate container for each marker primer pair. Amplify nucleic acids A preferred pair of primers for doing so was selected, SEQ ID NO: 1, SEQ ID NO: 2 SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8 , SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, Sequence No. 19, SEQ ID No. 20, SEQ ID No. 21, SEQ ID No. 22, SEQ ID No. 23, SEQ ID No. No. 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: Amplify the sequence identified in No. 34.   In another embodiment, such a kit comprises SEQ ID NO: 1, SEQ ID NO: 2, No. 3, SEQ ID No. 4, SEQ ID No. 5, SEQ ID No. 6, SEQ ID No. 7, SEQ ID No. 8, Sequence No. 9, SEQ ID No. 10, SEQ ID No. 11, SEQ ID No. 12, SEQ ID No. 13, SEQ ID No. 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 1 9, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24 , SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34 Specific to the gene contained in the polygenic trait corresponding to the sequence specified in C Includes hybridization probe. We have found that polymorphic alleles (which are May be diagnostic in the methods disclosed herein (especially the MAA technique). Suspicious) any ply known to be effective for hybridization It is envisaged that a mer could be used in such a kit. Such a kit Generally, in suitable means, for each individual reagent and enzyme, and for each Separate containers for marker primer hybridization probes Prepare.   A DNA segment encoding a specific gene is introduced into a recombinant host cell. And used to express specific structures or regulatory proteins. is there Alternatively, a part or derivative of a gene selected by applying genetic engineering technology used. An upstream region containing a regulatory region (eg, a promoter region) is isolated Obtained and subsequently used for expression of the selected gene.   The present invention is not limited to the particular probes disclosed herein, and in particular At least a nucleic acid sequence (which can hybridize to the disclosed sequences, or Functional sequence analogs of these sequences). You. For example, a partial sequence may be a structurally related gene or full-length genome or c Can be used to identify DNA clones from which partial sequences are derived . Those skilled in the art will recognize the cDNA and genomic libraries they produce (this is described above). Used as a target for the probe to be mounted (Sambrook et al., 1989). To get enough).   The nucleic acid segment of the present invention may be a plasmid, cosmid, or virus. For applications incorporated in vectors, these segments may contain other DNA sequences (eg, For example, promoters, polyadenylation signals, restriction sites, multiple cloning Site, other code segments, etc.). So these whole The length can vary considerably. Almost any length nucleic acid fragment is preferred Due to ease of preparation and use in the intended recombinant DNA protocol It is contemplated that it may be used with a limited total length.   Novel methodology for detecting multiple genes in one DNA sample   Many genes and their polymorphic loci are required for RDS and related behaviors Therefore, the present inventors have proposed a multigene screening (GENESCREEN).^TM) It is expected to sing. This is because of new DNA technologies (eg, AFFymetr) ix developed by GeneChip). In summary, the glass The tip is coated with a photosensitive chemical compound. These chemicals are added to the chip, And it contains light-sensitive protecting groups that prevent the binding of DNA bases to each other. However When light hits the chemical, the protecting group is inactivated and the chemical coupling A reaction can occur. Shine light on certain areas of the chip (but not on other areas) The use of "masks" allows DNA bases to be selected on the chip. It can be coupled to a selected area. Each new base that is added repeats the process And have an associated protecting group to couple one base to another You. In this method, a number of differently sequenced DNA probes are combined into a single 1/2 in. The same can be synthesized on a multichip.   Build any set of up to 400,000 probes up to 20 DNA bases in length Requires only 80 chemical steps to perform. Using a conventional DNA synthesizer To assemble probes with many different DNA sequences in a reasonable time frame. Is impossible. These machines are the large ones used by Affymetrix. Assemble the probe continuously rather than in a volume parallel fashion. This quick In DNA analysis, the sample DNA is first labeled with a fluorescent tag and then Is added to the probe array on the tip. The sample complements the complementary probe on the chip If found, it binds; if it does not find a complementary strand, wash off the chip The segment of DNA having complementary bases as described above so that it is complementary. They are themselves: for example, the fragment ATGCGC (SEQ ID NO: 1) has the sequence T Binds to a fragment complementary to AAACGCG (SEQ ID NO: 2). Each probe The sequence and position of are known. For this reason, the scanner will The lobe can be determined. Since the sequence of the probes on the chip is known, The sequence of DNA is also known. This sequence is therefore complementary. Genji Use of the template does not require copying messenger RNA to cDNA And one messenger rNA and cDNA can be quantitatively detected.   However, other assays that rely on DNA machines for the analysis provided in the present invention The method can be perfectly matched for commercial use. For example, genotypes by mass spectrometry available. Use DNA chip technology for many genes of the same genotype Alternatives for Sequenom (San Diego, CA) ) For the determination of abundant mass genotypes of single base pairs and short tandem repeat polymorphisms -Assisted laser desorption ionization time-of-fli matched for gh mass spectrometry (MALDI-TOF) was employed (Little et al., 199). 97). This is achieved by the following steps. First bind to one of the primers Biotin and polymorphic region PCR^TMAmplification is performed (Jurike et al., 1). 997). Second, immobilization of amplified DNA on streptavidin beads occurs ( Jurinke et al., 1997). Third, primers adjacent to the polymorphic site r, 1997). Fourth, polymorphisms in the presence of dNTPs and ddNTPs Stretch of DNA polymerase (which occurs in the presence of deoxy form) No) happens. When properly designed according to the sequence, this can The DNA is then treated to remove virgin DNA and salts. Sixth , Short primer + polymorphic site is removed by denaturation and piezo pipette And transferred to a silicon wafer (O'Donnell et al., 1997). Seventh Extracted MALDI-TOF material with delayed primer + polymorphic site mass Determined by quantitative analysis (Li et al., 1996; Tang et al., 1995). Array Single-strand base pairs and tandem repeat variations in DNA are easily determined by these masses. This final step is very fast, requiring only 5 seconds per assay Absent. All these steps are robotically automated. This technology is 1 Has the ability to perform genotyping up to 20,000 per day.   This technique is rapid, extremely accurate and adaptable to any polymorphism. You. This technique is much more accurate, with single-stranded base pairs and short tandem repeats. Polymorphisms that can identify both types and add or remove to be tested What can be done in seconds at a moderate price is a significant advantage over chip technology. Multi-gene kit-Gene screening test kit Depending on the gene, Table 2 below shows GENECHIP^TMInfluential remains based on the concept Describe the genetic disorder kit in detail.   All this should be done to safely identify the high risk rate for RDS behavior. It is our proposal that these genes must be tested. Other genes If they are found, it is expected that they will also be tested. Best for exams The first plan is PCR^TMIncluding technology. Because only a few genes make up the test panel This is because that. If these other genes are found, they may be GENECHI P^TM(Affirmatrix, Santa Clara, CA) Is done. Step 5. The fifth step was an independent study (which led to the highest quantitative score for the genotype). And indicates which genotype is associated with the lowest score) To evaluate the genotype score. Gene scoring is based on each polymorphism AN to test the magnitude of the average Kellgren score for each genotype Based on the use of OVA. These studies depend on the subject used for MAA Not performed on one set of subjects. For example, dopamine D_TwoReceptor Due to the TaqA1 / A2 polymorphism of the gene (DRD2), all studies Alleles are related within the areas of impulsivity, compulsiveness, and additional behavior. And some studies show that heterozygous genotype 12 has the highest score and The lowest scores indicate that they are associated with 11 and 22 genotypes. Therefore DR The D2 gene uses the TaqA1 / A2 polymorphism to generate genotype 22 or 11 = Scored as polymorphism with 0 and polymorphism with genotype 12 = 2. Independent studies showed that 22 genotypes had the lowest score for quantitative traits, with 12 Is the median score for the quantitative trait, and 11 is the one with the highest score. , The scores are 22 = 0, 12 = 1 and 11 = 2.   When dinucleotide or trinucleotide polymorphisms are used, Alleles are shorter, paired, longer, even when the gene is present It can be divided into alleles. Longer allele has the greatest phenotype If related to the effect, the scores are SS = 0, SL = 1 and LL = 2, where Where S is the shorter allele and L is the longer allele. Step 6. By adding scores for each gene progressively, it is possible to Or set up PG variables. For example, the score for the first gene tested is If the score is 1 for the second gene and the score is 1, The variable is 3. 1 to n cases for quantitative trait variable scores The correlation coefficient r of the regression analysis (which is preferably any off-the-self statistical Gram). The proportion of dispersion is r^TwoIt is. Then 1 For cases n to n, the gene score for the third gene is added and The leverage process is repeated. The final result is plotted. Step 7. Perform a univariate regression analysis of PG versus QT or DV. Below are any quantitative traits Or a generalized example for dichotomous variables. Before the analysis can begin, Apparent variables for the core (PG). = 0 is set. Then each further remains Genetic scores are added, regression analysis is performed, second gene scores are added, The inductive analysis is repeated. This means that all of the genes tested have It continues until it is done. For example, PG is initially set to zero. Gene 1 score Is equal to 2, the PG value is adjusted by 2 or PG = PG + 2. QT Or a regression of PG to DV is then performed. Gene 2 score equals 1 If so, then the PG value is adjusted by one, or PG = PG + 1. Or the remains If the score of Gene 2 was equal to 2, then the PG value would be adjusted accordingly Or PG = PG + 2. When the score of gene 2 is added, The regression analysis of PG vs. PG vs. QT or DV is performed again.   One preferred method for analyzing data is to use a statistical package such as SPSS. Entering all data into the page. As described under step 5 above Syntax values for the SPSS program using the values for the Open the file and set up the following sample algorithm.   Calculation PG = 0. (When DRD1 is equal to 2) PG = PG + 2. (When DRD2 is equal to 2) PG = PG + 2. (When DRD3 is equal to 2) PG = PG + 2. (When DRD4 is equal to 2) PG = PG + 2. (When DRD5 is equal to 2) PG = PG + 1. (When DRD5 is equal to 2) PG = PG + 2. (When DRD1 is equal to 2) PG = PG + 1. (When DRD1 is equal to 2) PG = PG + 2. Regression variable = ADHD PG / Dependency = ADHD / Method = ENTER PG   The PG variable is set to 0. DRD1, DRD2, DRD3 and DRD4 Since the gene is scored as 0 or 2, (subject is DRD1 DdeI 11 genotypes and / or DRD2 TaqI12 genotypes and / or DR D3 MscIll or 22 genotype, and / or DRD4 46,47 Or if they have 77 genotypes) they only increase PG to 2 Request a line. According to the comparison between the DRD5 gene and DAT1, the gene was 1 or Scores as 2 (requires two lines of code). Regression analysis shows that each gene Performed on PG score against QTV (ADHD score) as added Is done. Step 8. Plot the result. The results are shown in FIG. 5 (which is additive for AHDH). And the subtractive gene) as shown in the line R2 is plotted with the gene added and for the Y axis. Step 9. Repetition of the procedure using only the additive gene, which shows the additive gene in FIG. Is indicated by the line.                           Treatment of RDS-related behavior   By enhancing the efficacy of endogenous and / or exogenous neuronal peptides , A decrease in demand for euphoric drugs in certain anti-respiratory substances and in the nucleus accumbens Neurotransmitters such as dopamine release are abnormal abnormal behaviors, term "RDS" line Euphoria, alcohol, cocaine, opiate, nicotine Chin, glucose or other sugars, as well as specific effects (eg, sex, gaming, aggression) , And violence). RDS behavior is a common genetic The appropriate supply of neurotransmitters in the meso-limbic system Based on salary. The final route of reward is the receptor site (D1, D2, D3, D4, D5 And subtypes) and the density of these receptors Of each of these genes and dopamine, synthesis, storage, release and metabolism Determined by the causative gene.   The present invention relates to the inhibition of enkephalinase, the inhibition of kyotorphin (Tyr-Arg). Such an enkephalin releaser or a stable analog thereof, the D2 receptor Capable of multiplying or up-regulating (Fitz et al., 1994) TyrD-Arg-mediated synapse to promote chronic occupancy of D2 receptors The combination of the use of enhanced dopamine release is provided.   The present invention involves, in part, the invention of polygenic inheritance, and therefore high Promotes the concept of multiple loci as determinants for identifying risk candidates. Studies involving quantitative trait loci have been developed for one single genetic mechanism theory. Investigate genetically distinct mouse strains that provide negative evidence Fifteen strains of these mice have these alcohols, morphine and methamphetamine. Was tested for reactivity with These strains work on these three substances. It has been found to react dynamically. This is because different genes bind different habitual substrates. Determine the susceptibility. The pattern of knowledge is genetically affected for alcohol It further suggests that the sensitivity is not a monolithic phenomenon. Rather this is a laboratory Specific to the particular response variable sought (Crabbe et al., 1994).   Therefore, an aspect of the invention is a particular genotype of the above identified genes, Contribute to RDS behavior or other polygenic traits to obtain a monomorphic profile Other genes suspected of being targeted for RDS, related behavior, or other genetic traits Can be an important aspect of the treatment performed. Are specific genetic variants associated with behavioral disorders? If they have been identified, we will consider pharmacogenetically targeted treatments. Use this knowledge to assist clinicians in working. The present invention provides an anti-craving composition Genotyping and precursor amino acids for favorable enhancement of dopamine in No acid load, enkephalinase inhibition, enkephalin-induced release, narcotic antago Combination of chromium and the use of chromium picolinate or chromium nicotinate Let   In the present invention, we consider a reward cascade (which may be 100 or less). Changes in any of the genes involved in the expression of the molecule in RD May predispose individuals to S and related behaviors (including ADHD and even violence) You. While the above may be true, i.e. predict that a particular gene will be included It is very difficult at this time, but likewise the disclosure of the present invention Related to surgery. However, at least because of the law of the D2 dopamine receptor gene Is esoteric, and we have found that the D2 dopamine gene receptor We believe it provides important "reward genes" for DS and related behaviors. Preferred of the present invention A preferred embodiment is the TaqA1 DRD2 allele (A1 between exons 6-7). , B1, C1, haplotype polyplasia) and the outcome of the targeted treatment (ie, , Among other things, care, prevention of regained weight, cessation of smoking, reduction of carbohydrate glut, Reduced AMA rate, reduced multiple drug dependence course, and reduced violent behavior) It is to combine. The inventors have also found that the specific genes listed above (which Should give the best response to a particular drug class) Provide an example of a tradition.   In a neurotransmitter reward cascade model, hypothalamic serotonin production Utility neurons neurally utilize and activate met-enkephalin neurons, It is then gamma aminobutyric acid (GABA) neurons (which are then Activating DA neurons). Then these DA neurons Shows that Acb and the hippocampus (the neurotransmitter DA acts as a primary reward (Stein and Beluzzi, 1978)). CA1) Plan for cluster cells.   The nucleus accumbens and enkephalins in this complex circuit are important (Heidr eder et al., 1988). DA release in the striatum is determined by enkephalinase in Induced after topical application of inhibitor. This is due to delta receptor stimulation. Suggest a clause (Chesslett et al., 1981). In fact, Keratrufan In addition, cholecysteine-8 (cholecyst) which is possible by brain peptidase erkine-8 (CCK-8). This important satiety -Long peptide is co-localized with DA in the nucleus accumbens, and CCK-8, DA And there is a close interaction between endogenous opioid peptides (Koob , 1992).   Neurotransmitters serotonin (5-HT), DA, norepinephrine (NE ), And enkephalins have been shown to reduce sweet food intake. Accordingly, the compositions of the present invention are particularly suitable for the pre-expected acid loading (which is (5-HT precursor), 1-phenylalanine (DA and NE precursor) and Nkephalinase inhibitor d-phenylalanine (Blum et al., 1986) ) To enhance these food-blocking neuron transmitters. Measured.   Currently, the present inventors have conducted studies on Lewis rats, and these drugs have Tegory's effect has been established. Lewis rats have a propensity for multiple substance abuse Appear to serve as an important animal model for RDS behavior. This point , Three drugs (D-phenylalanine [DPA], naltrexone [NT X], Ty-D-Arg [TA]). Used for self-selection of either col, cocaine, nicotine, cannabis or sugar Have been. When comparing any combination of the other two drugs, three drugs The combination of agents together is most effective (see Table 3). Compositions for treating RDS. Various disorders are classified as belonging to the RDS, And all individuals that affect the dopaminergic system but suffer from RDS etc. No treatment. Numerous other systems can be affected and the whole to be achieved Require the same treatment for successful success. In particular, the disorder (this can be drug or drug Abuse) must be treated individually. Therefore, the overall treatment is dopami Effective dose of enkephalin inhibitor, enkefu Further components, including providing an amino acid releasing agent, and an amino acid precursor. Used to enhance the overall effect of the device.   Certain therapeutic agents are supported by "Gene D2 receptor deficiency theory" . It is sufficient that the DRD2A1 carrier has low levels of the DRD2 receptor. Is established. During stress, patients are facing these Requires a full supply of receptors. An important embodiment of the present invention is that certain precursors Body amino acids, chromium picolinate and / or chromium nicotinate Trace metals, enkephalinase inhibitors, narcotic antagonists And dopa for actually inducing D2 proliferation (particularly in D2A1 carriers) A therapeutic amount of an ekephalin-releasing agent (alone or in combination) to produce the natural release of Combination). This general concept has already been tested in cocaine addicts Have been. TROPAMINE^TMDeveloped by a previous inventor called Formulations have been studied and utilized in patients. TROPAMINE^TMIs Compared to other prescriptions and shows major benefits from both detoxification and retention (Halikas et al., 1993). See Table 4.   A component of this embodiment is to treat a patient of the first genotype, Provide an appropriate cocktail based on the genotype of the woman. D2 is unusual in the present invention They have developed the appropriate cocktails described herein. Table 5 shows the composition of the present invention. Uses are summarized as being improved with specific genotypes. Tables 6 to 16 Lists preferred components of these compositions useful for the treatment of various diseases . Also, referring to Tables 17 to 19, it can be seen that certain factors are stimulants (such as cocaine) and opiates. How do they affect the rewards induced by ate and sedative sleeping pills? It is a simple schematic diagram which shows whether it exerts. Annotation: Initiative on basic reward deficiency syndrome behavior generalized across symptoms They say (before meals) the "nuclear" neurotraceutical three times a day Is recommended. Patient has a series of persistent addictive / impacting / psychogenic Movement, or exhibiting pronounced heavy addictive / impacting / psychogenic behaviour. At the appropriate time of the day, the appropriate The administration of additional neuropharmaceutical packets is recommended. About obesity, the patient When she is directed to ingest the "core" neuropharmaceutical, Should take colored capsules. The patient turned orange before breakfast You should take capsules. For nicotine addiction, patient turns blue at bedtime Should be taken with a capsule.   Treatment method: In the present invention, D-phenylalanine containing hydrocinnamic acid, D-leu Syn, and any D-amino acids (see Tables 6-16) are included in the treatment formulation. In addition Thus, the enkephalinase inhibitor is included in a formulation that includes But not limited to: specific protein synthesis inhibitors (eg, bacitracin , Bestatin, and puromycin); peptide amino acids (eg, Mono-free amino acids, di- and tripeptides of essential amino acids in D-form); All benzyl amino acid (2- [mercapto-3-phenyl-propanoyl] -L-leucine ); Carboxyalkyl methyl ester (N-[(R, S) -2-carbethoxy-3-fe Nyl-propanoyl] -L-leucine); and numerous other structurally unrelated compounds (Eg, secobarbitol, pyrophosphate, O-phenanthroline , Phosphamidon, Z-leucine-NHOH, and Z-glycine-NHOH).   Furthermore, the present inventors have also provided by supplying an enkephalin releaser. , It has been found that patients' response to treatment can be dramatically improved. Therefore, Enkeffe Tyr-Arg and Tyr-D-Arg are also included in treatment formulations. I will.   Multiple genotype alleles lead to widespread impact, psychogenic, and addictive disorders If the general mechanism is affected by both stimulants and non-stimulants Cause a preferential release of dopamine (DA) into the inner core nucleus accumbens (Acb) Suggest. The genotype base of this mechanism is at least a polymorphic dopaminergic gene and And restriction enzymes (D1-D5, DAT1, DβH, MAOA, COMT); Modulates the neurotransmission of cardiods (including serotonin, enkephalin, GABA, and DA) Composition should have beneficial effects on drugs and behavioral disorders. You. Drugs of abuse and behavioral disorders include, but are not limited to: : Alcohol, cocaine, nicotine, glucose, cannabis, opiates and opiates Eate derivatives, gambling, sexual urges, hyperactivity, chronic violence and stress Disease, as well as symptoms associated with premenstrual syndrome (PMS).   To induce dopamine release in the core nucleus accumbens, opioid effects Activity is ultimately involved. Therefore, it binds enkephalinase inhibitors Can cause the enkephalin and the release of the enkephalin to collapse together And is expected to provide maximal enhancement of opioid action activity.   An important component of this embodiment is that for patients of the first genotype, Or provide an appropriate cocktail based on her genotype. In that D2 is unusual, We have developed the appropriate cocktails described herein.   Synthetic agonists are not preferred therapeutic agents. Some predetermined agonists Acts as a receptor for or similar receptor in different cells But can only act on certain receptors or cells that require stimulation There is no. (Changes in the affinity of a large number of receptors and their drugs for drugs As through) the resistance to the agonist may develop as well You. For example, the specific problem bromocriptine or methamphetamine is It can cause drug dependence on its own. Both bromocriptine are rhesus monkeys (Woolverton et al., 1984).   In contrast, intolerance was observed with D-phenylalanine (DPA). S.Ehrenpreis (Th e Chicago Medical School), the tolerance and addiction were at a dose of 500 mg / kg / day. This does not occur in mice to which this drug has been administered for a long time.   Further considerations for the combinations proposed herein are also Includes the understanding that a releaser is effective only if it has something to issue. So They will not treat dopamine deficiency conditions. In fact, the present inventors Worry that releaser alone may exacerbate chronic dopamine deficiency are doing. In this regard, the precursor uses a naturally regulated pathway. precursor Is converted to neurotransmitters only when needed, and then its body is based on need The product is distributed.   The prior art is in the treatment of alcoholism, cocaine dependence as an anti-craving part And the use of DPA. l-tryptophan, l-glutamine, and pyridox Data from Blum's group showing DPA use in combination with monkey 5 'phosphate Yes, it describes a 90-day open study for weight loss. In this survey The additional group averaged compared to just 10 pounds in the control 26 pounds down. In addition, only 18.2% of research groups have 81.8% In comparison to the rules, there was a reduction of less than £ 15 over 90 days. On the other hand, These results indicate that overweight individuals weigh 2.7 times more than patients without product benefits Is shown to decrease.   We have identified 247 outpatients on a low-calorie fasting program for two years. DPA and other compared to the central vitamin group alone Groups taking supplements containing low levels of amino acids and trace metals should: Was found. 1) In the proportion of overweight people for both men and women 2) a 70% decrease in desire for women and in men 63% reduction; 3) 66% reduction in bulimia for women and 41% reduction for men 4) the study group recovered only 14.7% of the weight they lost during fasting, The control group recovered only 41.7% of the lost weight; 5) Lodgis Logistic Cregression modeling is used for replenishment procedures, female Gender, morbid obesity, and family history of obesity significantly predict weight gain at 2 years It was shown that.   This data shows that DPA alone or other amino acid precursors, and chromium picotinate ( like chromium piccotinate) or chrominum niccotinate This dramatic effect, especially in combination with trace amounts of metals, can help prevent weight gain and Indicates that over 2 years of weight loss has the potential to eliminate recovery. to date, I know that there are no potential products on the market.   In addition, other studies have contributed to the understanding of the mechanism, which indicates that obese people lose weight. , And maintaining weight loss made it very difficult to interrupt subsequent weight loss therapy. These studies show how the body "protects" a given weight, often called the "target." To control it. Reduced energy expenditure during weight loss program In the face, target values are defined by the body: hunger increases, oxygen utilization decreases, The digestive system becomes more effective in absorbing nutrients, and Mon secretion decreases (Keesey, 1989). In addition, the weight may be affected by any intervention If you decrease, hygienically or pharmacotherapy will decrease, this is a stable weight or Can be one of the "plateaus", which many dieters describe. Being balanced, or gaining weight. Regarding this supply, it has recovered It not only keeps weight down, but also overcomes the plateau effect Looks like.   Fenfluramine alone and in combination with phentolamine vs PHENCAL^TMKen Ultimate comparison. Studies with d-fenfluramine found that they consumed food whenever they wanted Despite returning to normal levels, there is a sustained loss in weight. Hi Until recently, studies in both animals and animals have limited the rate of metabolism following drug administration. Failed to demonstrate an increase. Instead, when an increase in energy consumption occurs At any time, fenfluramine seems to increase energy expenditure (potentate) It is. This drug increases the effects of food heat in both humans and animals. Let Resistance does not seem to develop its potential for increasing energy consumption But this is not true about its potential to act as an appetite suppressant (Levitsky and Troiano, 1992).   The most important considerations in considering novel weight product The therapeutic effect is that recovery of weight loss must be prevented. In fact, Turn er indicates that permanent weight loss is the goal of a weight loss strategy and that Based on current evidence for this effect, d-fenfluramine is Weight loss effect over a period of up to 12 months without developing And prolonged use of other pharmacological drugs used in the treatment of this disease. There is a problem that it is limited. D-Fenflurami through a serotonergic system Study finds that weight loss in patients who do not respond satisfactorily to other weight loss strategies Following the longest study reported for D-fenfluramine, If weight loss is maintained, continuous treatment is required for severely overweight patients It is shown that. D-fenflurami in preventing recovery from weight loss Can vary between 13-25% due to a reduction in daily energy intake It is clear that it acts on d-fenfluramine is also a fatty food It also works by reducing appetite for food. d-amphetamine and other Because stimulants are approved, PHENCAL^TMFormulations are even better for weight loss We consider it to be generally accepted as an FDA-approved drug. We have found that amino acid precursor loading and enkephaliner The consequences of the use of zein suppression may be a tremendous step forward in reducing weight recovery Think.   A preferred embodiment of the treatment. Basic treatment therapies for RDS behavior include: Should contain at least one drug, alone or in combination (Table 20) . This table shows the majority of treatments, either in terms of drugs or "neuropharmaceuticals". (See Tables 6-16 for specific formulations).  Other enkephalinase inhibitors that may be useful in this treatment (see above) U.S. Patent Nos. 5,189,064, 4,761,429, and Canada See U.S. Patent No. 1,321,146. These are incorporated herein by reference. ).   Carbohydrate bingeing or anti-obesity compounds. In this regard, the previously mentioned Acid loading and enkephalinase inhibition are important in many cases related to weight problems. Affecting things, most importantly the prevention of weight regained after a two-year period is there.   Detailed Anti-SUD Protocol: Alcotrol as a Function of Genotype^TMAnd Cocotro l^TM. A public trial evaluation was conducted to determine whether both alcoholics and cocaine probands Amino acid precursor loading and enkephalinase inhibition in the prevention of recurrence in children The effectiveness of the harm was determined using a formula improved from the original patent. This research has been for two years A total of 280 patients observed over the period were included. Recurrence criteria are certified If the proband has alcohol or cocaine, as assessed by a Was back to regular use. Patients were divided into two groups: Group A = 1 Only one vitamin per day; Group B = various Alcotrols for alcoholics^TM And various cotrols for cocaine addicts^TM(See Table 8 for prescription And 9).   Two years later, a total of 78 patients in the control group relapsed two years later in the study This is an 86% recurrence rate. In the case of amino acids, a total of 189 patients None of them returned after a two year period. This means that with a 0% recurrence rate is there. This result has a very positive effect on preventing recurrence in SUD patients. Show. In essence, this effect is typical of the traditional 12-step recovery approach To improve the results seen in patients attending the appropriate treatment facility.   Typography of alcoholics and cocaine abusers: genotype A and And B-type proband. Researchers have classified alcoholics as type A or type B Has tested the concept of subtyping. And this time, we ’re studying cocaine abuse To find useful concepts. Subtyping shares one or more common features. A system for the classification and study of solids. Alcohol dependent sub Typing determines the genetic, personal, and environmental factors in the development of alcoholism. Complex interactions between risk factors and repulsion to yield to these risk factors Provide a greater understanding of.   Alcohol abuse is more pronounced in type B alcohol than in type A alcoholics. Severe among poisoned patients. Type B alcoholism has several features Seems to be: this is more associated with genetic factors than type A; this is in men Type B patients are more impulsive and Tend to have a stronger family history; they have more childhood conduct disorders and Due to severe alcohol dependence, multiple substance abuse, and psychiatric disorders, especially He has a personality.   For cocaine abusers, certain vulnerabilities (eg, alcohol abuse Family history of substance or substance abuse, sensation-seeking behavior, and small Childhood behavioral disorders) tend cocaine users to a more malignant form of cocaine-dependent type B It seems to let. Therefore, other cocaine abusers who do not have these properties [Type A] Are social or environmental influences associated with genetic, temperamental, or psychiatric effects. They may generate their cocaine dependence from the sound.   Important features of the three main properties, eg pre-disease risk factors [eg drug abuse Family history, pediatric sexual activity disorder and ADHD, sensory seeking traits, and drug abuse began Age]; variables of substance abuse [frequency of cocaine use, years of heavy cocaine use] Number, cocaine dependence, alcohol dependence, multiple drug use, and medical And social consequences]; and psychiatric problems [eg, depression symptoms and Social personality and the severity of these psychiatric problems] (Bell et al., 1995).   In addition, type B is associated with sensory seeking, aggression, criminal activity, violence, and social compatibility In the evaluation of the defect, a higher score than the type A was recorded. The former type also Use more cocaine more frequently and longer than type A cocaine abusers Used for a period. Patients with type B also have side effects from these uses (eg, consciousness Loss, and violence (among others)), and they suffer from withdrawal pain A greater degree of further substance abuse to mitigate was reported. Type B abusers First use, first overdose, first regular use, first daily use, and first addiction Because of the symptoms, you will have a relationship with cocaine at a younger age.   Length of time between first use of cocaine and first symptom of dependence; route of use ( E.g., nasal inhalation, smoking, or injection); used in controlled use attempts Number of strategies used; and prior to withdrawal from illegal drugs or alcohol No difference was found between the two subtypes for the time period. Interesting thing In addition, more than half of the stakeholders were classified as type A patients, The number of type A patients and type B patients was almost the same. Outpatient 75% were type A among those who were not treated and those who were not undergoing treatment.   One aspect of the present invention is to improve both alcoholism and cocaine abusers. Novel research using molecular genetic diagnosis for accurate typography and B-type Combine with previously identified indicators of nature. New genetic findings are surprising (Bell et al., 1995). DRD2 inheritance alone: The association with offspring alone is largely related to the B-type parameters suggested by Ball et al. (1995). Closely related to almost everything. The evidence provided is that of the dopamine D2 receptor gene. From numerous studies related to non-Hispanic white genotypes with polymorphism (See Table 20-A).   ADHD A major problem for probands with ADHD is that they have problems with focusing. It is to be. Our recent work is based on Kantroll^TMThose processes called Show that one of the commodities affects a number of electrophysiological outcomes (see Table 6A). thing).   This means that specific amino acids for performance-related cognitive event-related potential (ERP) First report of the effect of daily intake of the mixture, known to the inventors in humans It is a notice. Cognitive ERP consists of two computerized visual attention tasks: spatial Task-oriented tasks (SOT) and uncertain continuous execution tasks (CCPT) Produced in adult volunteers, where each subject has 28-30 days of The tests before and after ingestion of noic acid were performed under his own control. P300 component of ERP A statistically significant increase in amplitude was observed after both tasks (p <0.009) and This was seen after an improvement in the process speed (p <0.015). Book with normal controls The enhancement of neurological function observed in the study was due to RDS after taking amino acid supplementation. (Ie drug use disorder, attention deficit disorder, carbohydrate overdose) It is consistent with an increase in reinstatement.   This study was not achieved in ADHD probands. But the rationality is very strong No. Because a large number of cases of ADHD show reduced hyperactivity with amino acid combinations And positive results in terms of academic improvement. We have proposed DRD2 The A1 allele is also associated with P300 and AER and VER as previously pointed out in the present invention. With data that correlates to abnormalities in Comings on cannabis in p300 waves See also his study. Taken together, this is a specific formula (HyperGen^TMTable 12 Or at least an enkephalinase inhibitor (dl-phenylalanine) ) Creates a powerful case for treatment with Using this rationality, We also have the DRD2A allele and a standard computerized ADH called TOVA. Has data on the relevance to the D-test, which is currently being analyzed.   Attention processing failure. One aspect of the present invention is an attention processing disorder. disorder) and other RDS-related syndromes. We have defined this treatment as The fact that attention processing is governed by neurotransmitter function, and certain features Allogeneic neurotransmitters are responsible for normal brain cognitive function (which depends on certain precursor amino acids (Which could be adjusted). Brain electrophysiological machine An understanding of noh is an organism of chemical mediators known to be involved in attention processing. In a developmental phase.   One area of recent interest has been the small dependence on alcohol (as measured by the P300 wave). Cognitive impairment observed in infants and focus on patients diagnosed with ADD / ADHD It is poverty. Evidence in this regard is that many destructive childhoods and adults Behavioral disorders (ADHD, Tourette disorders, learning disorders, substance abuse, refractory abnormalities (defia nt) disorders, and behavioral disorders) have strong genetic components (r-related) the concept of being part of the scope of action, dopamine, serotonin and others Are polygenic, sharing many common genes that affect neurotransmitters And the concept of being communicated by parents. Lack of insight Concentration on fall / hyperactivity causes ADHD to impair autoregulation or executive functioning The notion that it is most behaviorally characterized is supported. Anatomical nerve Mazing studies have shown that the relevant regulatory circuits are located in the prefrontal cortex and basal ganglia (the By dopaminergic innervation from and agonist activity or dopamine Excitatory drug therapy that activates dopaminergic receptors by either release Is regulated by).   The present invention also relates to neurotransmitters that produce innate dopamine release that overcomes PHD Composition of substances that promote quality manipulation and through the occupation of synapses by dopamine Dopamine D_TwoComposition of a substance that promotes receptor proliferation (use of phenylalanine Including).   Serotonin precursor. Serotonin (5-hydroxytryptoamine, 5HTP) CNS It is a neurotransmitter. This is also In the intestinal enterochromaffin system, And And found in platelets. This neurochemical is First, add L-tryptophan to water Oxidized to give 5-hydroxytryptophan, Then Decarboxylate the latter and make serotoni Is biosynthesized by obtaining Hydroxidation (the rate limiting step) The enzyme tryptopha Performed by hydroxylase, on the other hand, Decarboxylation is The ubiquitous enzyme L-aromatic acid Achieved by carboxylase. This enzyme Pyridoxal as cofactor Requires phosphoric acid.   Serotonin is By monoamine oxidase, 5-hydroxyindole vinegar Metabolized to acids. Then This metabolism Excreted in urine. Central brain serotoni Mechanism Mood and behavior, Athletic activity, Regulation of eating and hunger, Thermoregulation, Sleep Sleep, Certain hallucinations, And possibly some neuroendocrine in the hypothalamus Adjustment mechanism, May be important in the regulation of   Long-term use of cocaine Decreases the concentration of serotonin and its metabolites. Cocaine is clearly, Reduced uptake of tryptophan, a serotonin precursor Let This allows Reduces serotonin synthesis. Cocaine also Tryptopha Also reduces hydroxylase activity. Therefore, Cocaine is Serotonin action Reduce action (Reith et al., 1985).   Drugs that deplete serotonin (fenfluramine, PCPA or 5-7-DHT) Treatment of rats Both enkephalin and endorphin in the hypothalamus Increased the content of There was no increase in brain areas. mRNA or precursor At any content of proenkephalin (PE) or propiomelanocortin Also did not change, Serotoninergic transmission Without affecting synthesis , It has been suggested that they regulate opioid peptide utilization (Schwartz et al. 1985 ).   This finding, Due to the reduced enkephalin release, Dopa obvious as depressed Supports the hypothesis that it results in a decrease in min activity. After intense exercise, Specific row Dynamic defects occur, This includes pain, Depression, And sleep disorders. Seroto Recovery of ninergic transmission with L-tryptophan Recover positive mood Should help. Feeding tryptophan in the diet (ie, precursor Body loading) Clearly affected brain metabolism of serotonin and related compounds (Moir And Eccleston, 1968). The serotonin content of the brain is Plasma tryptophan levels (Fernstrom and Wurtman, 1971). Diet poor in tryptophan Rats given Have low serotonin levels in the brain, And L-bird Putphan remedied this deficiency. When tryptophan is injected into the bloodstream, Tryptophan and serotonin levels in the brain Respectively, 9 times and It rose twice. Tryptophan in psychiatric patients with both depression and insomnia The injection of fan Caused a 6-fold increase in cortical tryptophan levels (Gillman et al. , 1981).   Tryptophan (50 mg / kg) and tyrosine (100 mg / kg) or placebo, 8 people In a double-blind crossover study in healthy males (Lieberman et al., 1983). bird Putphan significantly reduced pain discrimination, Tyrosine did not decrease. other The research of Tryptophan reduces clinical pain (Seltzer et al., 1983), migraine (Poloni et al., 1974), And reversed painless tolerance (Hosobuchi et al. 1980 )It revealed that. By tryptophan via serotonergic activation , It appears that endorphin-acting release, which produces painlessness, is enhanced.   Unlike tyrosine hydroxylase, Under normal physiological conditions, Tryptophan Hydroxylase is not saturated. That is, This enzyme Works to full capacity Not Therefore, Tryptophan hydroxylase activity L-tryptophan Significantly affected by The amount of free L-tryptophan available is Many Depends on the factor of This includes In the uptake rate in the brain and presynaptic terminals Examples include the concentration of L-tryptophan circulating in plasma. We have: L- Using tryptophan or 5HTP Serotonin destroyed by cocaine It is intended to restore the active system.   5HTP is Not useful as a therapeutic. The rate of penetration of L-tryptophan into the brain is Depending on the ratio of free tryptophan to bound tryptophan in plasma, Soshi The leverage ratio is Neutral amino acids, Insulin, And pharmaceutical drugs (these are Plasma tan Competing for the park binding site and the tryptophan uptake site) Affected by concentration. Also, 5HTP is New non 5HT neurons Taken up by Ron; Therefore, The increase in 5HT synthesis is Serotoninnu Is not selectively limited to RON.   Inhibitors of enzymes involved in 5HT synthesis include: Irreversible tryptophan hydro Xylase inhibitors (DL-parachlorophenylalanine, 6-fluorotripp Tofan, And L-propyldoracetamide) Line 5HTP decarboxylase inhibitors (carbidopa and 1-methyl-5HTP) No. Serotonin is In response to action potentials and drugs, Exocytosis Process, It can be released into the synaptic cleft. The promotion of 5HT release is cocaine , (+)-Amphetamine, Methamphetamine, Fenfluramine, Parachloroa N Fetamine, Clorimipramine (clomipramine ne)) and amitriptyline.   There are three types of 5HT receptors (5HT-1, -2 and -3) have been proposed. 5HT Receptor agonists include: LSD, Quipazine, N, N-dimethyl trypto Amines (DMT). 5HT receptor antagonists include: Cyproheptadi , Methysergide, LSD, 2-bromo-CSD (BOL), Ketanserin, Xylamidine, Sinanserin, And 1-(-)-cocaine. Inactivation of 5HT High affinity Involved in energy-dependent active transport mechanisms, This is a presynaptic descent from the synaptic cleft. Exists to bring 5HT back to Hurong.   Inhibitors of 5HT neuron uptake include: Tricyclic antidepressants (imipramine , Desimipramine, Amitriptyline, Chlorimipramine, Fluvoxamine), Fenfluramine (appetite suppressant), And cocaine You. Any 5HT not bound during storage Converted to metabolites by MAO. I Scarecrow, If you inhibit MAO, Serotonin is O-methyltransferase (COMT) By N-methyl, Or N, Metabolized to N-dimethyl.   Opioid peptide enhancer / releaser. One aspect of the invention is: God The use of substances that inhibit the destruction of opiates of transpeptides. These opiates Is Promotes dopamine synthesis and release. Administration of opiate-like substances to animals But, Striatal DA biosynthesis and metabolism (identification located at nigrostriatal dopaminergic terminals) Increased the rate of opiate receptor-mediated effects). (Clouet et al., 1970; Biggio et al. 1978; Regiawi, 1980). β-endl For long-term fin or enkephalin administration, Develops topaminergic resistance (Iwatsubo et al. 1975; Arden, 1972). Post-synaptic DA receptors To resistant animals (Schwartz et al., 1978).   Cocaine also It also affects opioid action. Long cocaine in rats Exposure to A dose-dependent change in naloxone binding was observed. Opiate The receptor density is Markedly reduced in some brain structures, Hypothalamic outside In the field. The opiate bond is "Reward centers" And specifically affect It had no effect in other areas (Hammer et al., 1987). further, In another study, Naloxone Low cocaine threshold in brain reward center Effectively blocked hypofunction (Bain and Korwetsky, 1987). further, Coca The Inn It appears to affect the analgesic effects of certain opiates (Misra et al., 1 987). We have: Cocaine's potentiating effect In the brain reward center, Opie Can be partially mediated by It changes with prolonged cocaine exposure I believe.   Narcotic drugs Found to act on various "opiate receptors" Was done. The brain and other nerve tissue Found to have endogenous opioids (EO) Was. Related pentapeptides, Methionine and leucine-enkephalin , Identified in the brain (Hughes et al., 1975). Enkephalin is δ receptor And both μ receptor on the other hand, β-endorphin is ε receptor Activate the monitor. Endocrinologists, B-lipo already recognized as a pituitary hormone Tropine (B-LPH) Including a Met-enkephalin sequence of 5 amino acids, And that B-LPH was hydrolyzed to the active opioid β-endorphin (Li et al., 1976).   Current, We have: At least three EOs with different origins and different functions Knows one chemical system, All peptides have Tyr-Gly-Gly-Ph at their N-terminus Includes e-X sequence. The endorphin strain is Large precursors, Pro-opiocortin , B-LPH, And β-endorphin. The second line of EO is Enkephalin System. Both [Met] enkephalin and [Leu] enkephalin Both Derived from a large peptide precursor containing the sequence. Carboxy powder of enkephalin Hexapeptides having one or two basic amino acids attached to the ends and Epta peptide, And the heptapeptide ([Met] enkephalin-Arg-Phe) It appears to form an intermediate naturally (Hexum et al., 1980). The third strain is κ Agoni Strike (for example, Dynorphins 1-13 and 1-17). These CNS components Is Antagonizes morphine action. Dynorphin Leu-Enke forming N-terminus May act as a precursor of farin; Then Sub-endorphin form (E5) The conversion is Causes a change in receptor affinity (from κ to δ), This is an enzyme regulatory ligand Expression Here are the possible new regulators.   Peptides from each strain are: Both as neurotransmitters and as neurohormones Seems to work in one direction. The pentapeptide enkephalin is Localized to nerve endings And It is released from neurons upon stimulation. Leu- and Met-enkephalin Is Released into the blood from the adrenal cortex, Acts as a neurohormone. β-endl Fins Released into the blood from the pituitary gland, And this is Smell in dispersed areas of the brain hand, Can act as a neurotransmitter (Bloom et al., 1978). Endorphins and Both enkephalins Narcotic analgesics when EO is administered to humans or animals Similar to that produced by Produce biochemical and pharmacological responses, this In Resistance, Dependence, And withdrawal. Endogenous opiates, such as narcotic drugs The He is a member of the "opioid" class. Degrades enkephalin (E5) Enzyme In general, It is called "enkephalinase".   Various peptidases whose tissues metabolize pentapeptidyl dienkephalin (E5) Is well established. Enzymes that act as enkephalinases , Soluble and particulate bound aminopeptidase (Hersh, 1981), And Peptidyl dipeptidase or metalloendopeptidase (Benuck et al., 1982; S chwartz et al. 1980), as well as other enzymes acting at the Gly3-Phe4 site. Metal enzyme Carboxypeptidase A is Cleaving enkephalin, Try-Gly-Gly-C , And the terminal dipeptide is Met-Phe or Leu-Phe. Single enzyme targeted Unlike biogenic amines, which are a major cause of inactivation at the site, Minutes of enkephalin The solution involves several enzymes, Metallo endopeptidase is the major enkepha It seems to be linase. The following scheme is Action of enzymes related to E5 degradation The site is exemplified.   One strategy for dealing with decomposition is It is to provide a substitute for E5. Enke About Farin, Some chemical modifications block tissue enzyme degradation Is necessary for These include: a) Methionine enkephalinase degradation N-terminal-Tyr modifications for tyrosine-modified analogs of resistance (Coy and Kastin, 1980) ; b) of the D-amino acid at position 2 to block the effect of aminopeptidase Existence: And / or c) peptidyl dipeptidase acting at the Gly3-Phe4 bond Or modification of D-amino acids at positions 3-5 to block the action of other enzymes or Exists. Other analogs may include: As a μ agonist, D-Ala-Enke Falamide or FK 33-824; Δ agonists such as enkephalin-Arg-Phe ; And dynorphin 1-13 or 1-17 (these are kappa agonists (Wisler et al. , 1981)).   These drugs, which are candidate E5 agonists, Potential addictive disorders, Resistant and it Whether it has other toxicological problems associated with their clinical use is currently unknown. Possible addictive issues for many of these modified enzyme-resistant surrogates are: this Significantly reduce their clinical application.   For the enhancement of enkephalin or endorphin action in vivo Two and preferred strategies are: By using specific enzyme inhibitors is there. Certain enkephalin fragments (Gly-Gly-Phe-Met or Gly-Gly-Phe- Leu, Phe-Met, Phe-Leu) Can act as an inhibitor of enkephalin, So Appear to form larger enkephalin types than themselves and have inhibitory properties is there.   In the present invention, The term “enkephalinase inhibitor” includes: D-phenyl Alanine (DPA), DL-phenylalanine (DLPA), Hydrocinnamic acid, And D-Loisi D-amino acids such as It is not limited to these. Other enkepha Linase inhibitors are specific protein synthesis inhibitors (bacitracin, Be Statins, And puromycin), Peptide amino acids (free, D-form monoa Amino acids, Essential amino acids of D-form di- and tripeptides, Thiol benzil Amino acids, (For example, 2- [mercapto-3-phenylpropanoyl] -L-leucine), Cal Boxyl alkyl methyl ester, N-[(R, (S) -2-carbethoxy-3- [Phenylpropanol] -L leucine), Benzomorphan-enkephalin (enkap halin) Secobarbital, Pyrophosphoric acid, o-phenanthroline, Phosfami Don, Z-leucine-NHOH, And structurally unrelated compounds like Z-glycine-NHOH object, Expected to be selected from the group consisting of: Dipeptide D-Phe-D-Leu and D-P he-D-Met and polypeptides L-Tyr-Gly-Gly-D-Phe-D-Leu and L-Tyr-Gly-Gly -D-Phe-D-Met D-Phe, D-Leu, And certain eyes together with hydrocinnamic acid Become   D-phenylalanine is carboxypeptidase A (Hartruck and Lipscomb, 1 971) and more recently analgesic properties (Ehrenpreis et al., 1978; Della Bella et al. 1979 ) And antidepressant (Beckmann et al., 1977).   To evaluate the efficacy of D-phenylalanine as an inhibitor of enkephalinase To do The compound is an oligopeptide (D-Ala2-D-Leu5) Nkephalin (DAPLE) and Tyr-D-Ala-Gly-Phe (TAAGP) degradation are actually significantly reduced (Gail et al., 1983). But, D-phenylalanine from bovine brain Inhibition against the activity of both the resulting enkephalinase A and enkephalinase B When studied in vitro for harmful activity, Had very little effect (A msterdam et al. 1983). Interestingly, After forming the dipeptide D-Phe-Tyr The addition of one amino acid Significantly enhances inhibitory potency.   D-Phenylalanine blocks the degradation of both enkephalin and β-endorphin It has been shown to harm. that is, Compared to enzyme-regulated β-endorphin If Works better in enzyme-regulated enkephalin degradation. Its activity Also, Tissue-specific; In the hypothalamus, Enkephalinase is 80% inhibited And Endorphinase is inhibited by 5%; In the cortex, Enkephalinase Is inhibited by 60%, Endorphinase is inhibited by only 18%; Striated smell hand, Enkephalinase is 78% inhibited, Endorphinase is inhibited by 10% ; And in the spinal cord, Enkephalinase is inhibited by 84% Endorphina Is inhibited by 40% (Ehrenpreis et al., 1981). Other studies have [Met] -Enkefari The actual increase in CNS tripled within 90 minutes after DPA injection, And six days later (Balagot et al., 1983). [Met] -Enke in mouse brain Another increase in Farin Hydrocinnamic acid, Known metabolites of D-phenylalanine Was also found using.   Another aspect of the invention is Enkephalin-releasing reagents and enkephalinase inhibitors Is to combine The basis for this is By doing so, The inventor Et al. For each opiate receptor site (e.g., δ or μ). That is, the effect of kephalin could be significantly enhanced. Achieve this goal for, We have: Peptide Tyr-Arg (Kyotorphin), Or its stability It is preferable to use analog Tyr-D-Arg, This is analgesic, And Increases intracellular calcium in synaplosomes in striatum slices It is shown to be. These substances are Putative methionine acting by unknown mechanism -Seems to be an enkephalin releaser (Ueda et al., 1986).   Enkephalinase inhibition and enhanced neuronal enkephalin release To provide both A substance known as Kyotorphin (Tyr-Arg) 1 Daily dosages ranging from 5 μg to 15 mg can be used (Takagi et al., 1979). More stable The analog Tyr-D-Arg Enkephalin at daily dosages ranging from 15 μg to 15 mg Can be substituted as a releaser (Tajima et al., 1980; Ueda et al. 1986). Therefore, Enkephalin Releaser, Combined with enkephalinase inhibitor hand, Achieve a high degree of enkephalinrgic activity at the synapse, Neuro The release of renal dopamine can be further increased. This is a form of "replacement therapy" Act as And "desire" for cocaine, And disclosed herein Reduce other RDS behavior. This action After detoxifying cocaine, Most valuable in 12 months It is for.   Precursor for γ-aminobutyric acid (GABA). GABA is an inhibitory neurotransmitter, It controls the release of dopamine (Gessa et al., 1985). this is, Alcohol withdrawal Seems to reduce seizure activity. The main synthetic route to γ-aminobutyric acid (GABA) , Through decarboxylation of L-glutamic acid by glutamate decarboxylase (GAD) ing. Like other amino acid decarboxylase, This enzyme is a bifactor as a cofactor. Requires Tamine B6 (pyridoxal phosphate). GAD is synaptic for GABA nerve endings It is found only in the cytoplasm. The basic control of GABA synthesis is GAD, this is , It appears to be the rate-limiting step in GABA synthesis. GABA is FAD due to end product inhibition May affect activity. L-glutamic acid saturates are present in presynaptic neurons. Exists; Therefore, Increased substance concentrations do not normally affect the rate of GABA synthesis No. therefore, Exogenous administration of L-glutamic acid results in abnormally low L-glutamic acid levels Unless The neurotransmitter GABA may not be significantly increased. But, Different To adult albino rats with alcohol motives Glutami using drinking water (1 (500 ng / kg per day) for 10 days, Glutamate in the brain, GABA and And a significant increase in taurine content (Blum et al., 1991). Glutamine from the brain An active intermediate in the transport of ammonia, Therefore, differences in neural tissue Can greatly affect the catabolism of certain amino acids (Ostrovsky, 1984). After deamination , Glutamine is a precursor of glutamate, Therefore, it can be GABA (Thawki et al., 1 983).   There are at least two types of GABA receptors: GABA-A receptor Competitive blocking action of bicuculline and picrotoxin or picrotoxinin Sensitive to These receptors are In the post-synaptic structure, And GABA Mediates classical inhibitory effects; And GABA-B receptor Ranked presynaptic terminal Place And these receptors are sensitive to the blocker action of bicuculline . GABA-B receptors are not only GABA in the CNS but also NEs from specific sites in the sympathetic nervous system. Release can be modified.   Certain clinical dysfunctions are movement disorders, Huntington's chorea, Epilepsy and Arco It has been suggested that it may be involved in the GABA system, such as intestinal dependence. GA to GABA BA receptor, Benzodiazepine binding site for benzodiazepine and also Changes in the affinity of the barbituric acid binding site for barbituric acid Ta It is regulated by the protein "GABA-modulin". GABA-Module Phosphorus GTP-regulated proteins associated with receptors that bind to adenylate cyclase It is similar to the texture. The activity of GABA-modulin is It is measured by phosphorylation.   GABA is Typically, Hypothalamus, Hippocampus, Basal ganglia of the brain, In the glue of the dorsal horn of the spinal cord And associated with short inhibitory neurons in the retina. Some heads in the CNS The axonal pathway has been identified as being associated with GABAergic activity.   GABA agonists include: Imidazole acetic acid, 3-aminopropanesulfonic acid, And And THIP (4, Five, 6, 7, -Tetrahydro-isoyazolo- [415-C] -pyridin-3-o Tool, And muscimol (3-hydroxy-5-amino-methylisoxazole) And This is found in fly agaric. GABA antagonists include: Bi Kuklin, Picrotoxin, Picrotoxynin and benzylpenicillin Can be   High affinity sodium dependence in the presence of presynaptic GABA nerve endings and glial elements There is an uptake system, It is released by removing GABA from the extracellular space Inactivate GABA. Inhibitors of GABA uptake include: Neuron uptake type about, Diaminobutyric acid and cis-2, 3 aminocyclohexane, carboxylic acid; For glial uptake type, β-alanine; And miscellaneous uptake types The Nipecoic acid, Benzodiazepine, Including neuroleptics and tricyclic antidepressants You.   GABA returned into presynaptic neurons after release and receptor interaction , Reused as a potentially reusable transmitter. GABA is Nerve endings and guri It is metabolized enzymatically in both tissues, And Presence of A-oxoglutamic acid Under the mitochondrial enzyme GABA aminotransferase (GABA-T) Converted to acid (succini) semialdehyde. The succinic acid formed is Tricarbo Enter the Krebs cycle. GABA-T requires pyridoxal phosphate as a cofactor You. Succinic semialdehyde is The enzyme succinic semialdehyde dehydrogen Easily oxidized to succinic acid by the enzyme, This enzyme also has NAD and And NADH. Our formulation for RDS is: Promoting the redox pathway Take this fact into account by adding pyridoxal 5-phosphate as a ter .   In this regard, GABA concentration is For animals (including humans) The following inhibitors of GABA-T Can be increased by the administration of: Ethanolamine (P-sulfe) , γ-acetylene GABA, gamma vinyl GABA, Gabcuculline, gabcuculline, Hidor Dinobutyric acid (hydazinopropionic acid), Sodium di-N-propylacetate (valproic acid Sodium) and aminooxyacetic acid (an inhibitor of vitamin B6), L-glutami (Bloom, 1985).   Catecholamines (dopamine, Norepinephrine). Catechol Dopamine (DA), which is an amine, Norepinephrine (NE) and epinephrine (E) All are neurotransmitters. Catecholamines Two adjacent on the benzene ring It is a compound having a hydroxyl group (OH). In the body, Such substances are Aromatic amino acids Synthesized from L-tyrosine, This is the enzyme tyrosine hydroxacylase By L-3, Hydroxylation to 4-dihydroxyphenylalanine (L-dopa) Is done. L-tyrosine Actively incorporated into noradrenergic nerve endings You. L-phenylalanine is It is a precursor of L-tyrosine (Blum and Kozlowski, 1990; Schwartz et al. 1992).   Tyrosine hydroxylase is In the cytoplasm of noradrenergic neurons Position to, It is the rate-limiting enzyme in the synthesis of NE. Extensive research has Pteridine cofactor Decrease, Oxygen molecules and iron (II) ions Reveal that everything is needed for activity are doing. In the cytoplasm, L-Dopa is produced by L-aromatic amino acid decarboxylase. Is decarbonated by DA This enzyme has pyridoxal phosphate (vitamin B6) as a cofactor Need. Dopamine (DA) Actively taken up by granule storage vesicles, here, This DA is hydroxylated by the enzyme dopamine-B hydroxylase, No Forms lupinephrine (NE). This enzyme copper, molecule, As oxygen and cofactors Need ascorbic acid. In some neurons of the CNS, NE is And the enzyme phenylethanolamine-N-methyltransferase Converted to epinephrine (E).   Tyrosine hydroxylase activity is Affected by: "Final product" Inhibition, This is the concentration of NE in nerve endings that reduces the rate of conversion of L-tyrosine to L-dopa increase of; Increased sympathetic activity from the CNS that increases the synthesis of NE; NE synthesis speed Ngiotensin II-mediated increase; And adrenaline at presynaptic terminals Agonists that alter the rate of NE release by a mechanism involving phosphorylated receptors (E.g. clonidine) and blockers (e.g. phentolamine) Is done.   Inhibitors of NE synthesis enzymes Including: Methyl-p-tyrosine (tyrosine Inhibits droxylase); Carbidopa (aromatic amino acids in tissues outside the CNS) Noic acid decarboxylase); And diethyl dithiocarbonate, F AI63 and disulfiram (inhibitors of dopamine-B-hydroxylase).   NE is stored in nerve endings in more than one anatomical location in multiple storage complexes You. One form of NE storage type is Small in noradrenergic nerve endings It is a granular complex found in the vesicle. This granular complex is NE bound to ATP, Consists of several proteins collectively called chromogranins, Dopamine-B-Hide Roxylase and Mg ++, Including Zn ++ and Cu ++.   Uptake of DA and NE into storage vesicles An active transport process, This is energy ATP as a source of energy, To activate ATPase enzymes that are dependent on Mg and Mg ++ Requires Mg ++. This Mg ++-dependent uptake process of NE and DA into storage vesicles Is Separate from the neuron uptake process for NEs across the nerve cell membrane And a different process, This is Na. sup. + / K. sup. + ATP dependent.   The stability of the NE-ATP-protein-ion storage complex was created as a chelating agent for Mg ++. Can be destroyed by some compounds used. This is sometimes a chronic cocaine insult. May be related to magnesium deficiency found in users. In this regard, the long term cocaine Administration causes an increase in NE turnover.   The release of NE from nerve endings occurs through the process of exocytosis, It is calcium-dependent, whereby the vesicle membrane fuses with the plasma membrane and Cell content (consisting of NE, ATP, dopamine-B hydroxylase and chromogranin ) Is released into the synaptic cleft. Regulates the use of NE for postsynaptic receptors One known mechanism for the release is the presynaptic receptor located at the end of release of the NE. Actuated by the The action of NE in the synaptic cleft is associated with presynaptic nerve endings. It is terminated by removal from the synaptic cleft by the found uptake system. There are two types of neuronal uptake of NE, uptake I and uptake II.   Uptake I is energy-dependent and destroyed by sodium-dependent ATPase Need ATP. This is a high-affinity process, Efficient at low concentrations of NE eliminated. Uptake of neurons The system transports NE to nerve endings. In nerve endings, most NEs are storage vesicles Is taken into. Inhibitors of this process include: cocaine , Tricyclic antidepressants, amphetamine and tyramine.   Uptake II involves the accumulation of NE by non-neural tissues. From adrenal medulla irritation High plasma levels of NE or intravenous injection of catecholamines may It is removed by incorporation into non-neural tissues such as synovial tissue. NE or other cat Coalamine is either diffused back into the circulatory system or, more commonly, an enzyme. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) destroys cells.   MAO is found in all tissues, including mitochondria, and is associated with its outer membrane. It is. MAO is present in the liver, nerves, muscle and all active metabolic tissues. that is Oxidatively deaminates NE to c, 4-dihydroxymandelic acid, which in turn (By COMT) to give 3-methoxy-4-hydroxy-mandelic acid. Real Sometimes, MAOs are described as a group of isoenzymes, which represent different tissue distributions, substrate specificities, Has inhibitor and physical properties. For example, MAO A goes to NE and 5HT With a substrate preference and is selectively inhibited by clorgyline. MAO B Has a substrate preference for olopamine and phenylethylamine, And selectively inhibited by deprenyl (seledinine). Other well-known MAO Inhi Bitters are iproniazid, nialamide, pargyline, trunk lipromine (tranc lypromine) and phenelzine.   COMT is found in large amounts in liver cells. In the CNS, COMT acts on E and NE , Which are not inactivated by neuronal reuptake. Is an inhibitor Pyrogallol has S-adenosyl-L-methyl at the 3 'position of the catechol ring of NE, E and DA. To block COMT-dependent transport of methyl groups from onines to hydroxyl groups Therefore works. Dopamine is a precursor of NE and E and is found in the CNS and autonomic nervous system. Plays an important role in some ganglia.   High levels of DA in neurons may lead to tyrosine hydroxylase Inhibits and therefore reduces the rate of DA synthesis. Furthermore, the rate-limiting step in DA synthesis is Conversion of tyrosine to L-dopa by hydroxylase. Under normal conditions , Tyrosine hydroxylase is completely saturated with L-tyrosine and therefore circulates Increasing tyrosine levels does not increase the rate of DA synthesis. However, because of the lack of DA And tyrosine hydroxylase is impaired due to cocaine effects In both cases, this fact changes.   L-Dopa is actively taken up by DA neurons in the CNS, where it is converted to DA. It is. After L-Dopa treatment, there is a marked increase in the amount of synthesized and stored DA I do. By comparing with dopaminergic systems, the synthesis of NE after L-dopa treatment was And there is a relatively slight increase.   Dopamine is stored in storage granules, where catecholamines are chromogranins, Complexes with divalent metal ions and ATP. DA synapses by excitement It is considered to be released into the gap. As in the case of NE, this is calcium dependent Process in response to action potentials or drugs that reach nerve endings Occurs. The following substances may increase DA release; cocaine, (+)-amphetamine, Methylamphetamine, tyramine, amantadine, m-phenmetrazine, phen Theremin and nomifensin. In addition to DA release occurring, these compounds An agent can also inhibit neuronal reuptake of DA to different degrees.   After DA is released into the synaptic cleft, its effects are affected by the neuronal reuptake system. The system is terminated by a high-affinity, energy-dependent active transport process. Is. This system is similar to that already described for NE. MAO And COMT are both 3,4-dihydroxyphenylacetic acid (DOPAC) and Responsible for conversion of DA to movanillic acid (HVA, 3-methoxy-4-hydroxyphenylacetic acid) ing. By blocking DA reuptake into presynaptic nerve endings, Cain prolongs the effect of released DA in the synaptic cleft.   Elevated brain tyrosine levels result in increased L-DOPA synthesis in the brain. Then L-DO PA is metabolized to dopamine. Dopamine synthesis and release occur after tyrosine administration Will be increased. Dietary tyrosine without increasing catecholamine levels Increases dopamine and norepinephrine turnover and release. stress Cold, or certain drugs induce an increase in nerve excitation and catecholism in nerve endings Lower the levels of amines.   L-phenylalanine is an essential amino acid, which is also a neurotransmitter It is a precursor for the synthesis of pamine and norepinephrine. These metabolites These neurotransmitters, as measured by HVA, HVAC, DOPAC, and MHPH, It is significantly changed during periods of good exercise and physical endurance. L-phenylalanine is Used in place of or in combination with L-tyrosine or L-dopa, dopamine storage Can be recovered after deficiency by cocaine abusers.   The use of these precursors is a dopaminergic releaser, blocker, agonis Or dopamine, norepinephrine or epinephrine Can be supplemented at the appropriate time of treatment with agents that affect phosphorus reuptake or degradation You. But and more importantly, dopaminergic, including synthesis and release The overall range of activity depends on the particular opioid peptide (e.g., enkephalin and Endorphin). Opioi administered centrally Peptide (endorphin and enkephalin) is found in animal and human plasma Results in increased levels of catecholamines (Clouet, 1982). In fact, synapses Blocking pre-dopaminergic receptors enhances β-endorphin release Occur and show unique interrelationships. The compound that can be used as a precursor is L-tyrosine , L-phenylalanine and pharmaline.   Rhodiola rhosea extract (pharmaline) Rhodiola rosea, or Golden Root Perennial plant of the family Orpine (Crassulaceae), growing in the Arctic and alpine regions It is. In the Altai Mountains, eastern Siberia, Tien-sdhein, and in the Far East, Rho The cultivation of diola rosea has been successfully mastered. It, from seeds and plants It is possible to regenerate both by sexual methods (Polozhy et al., 1985; Saratoko v and Krasnov, 1987). Rhizomes contain phenolic compounds, most notably the most important Is the p-oxyphenylethanol (which determines the biological activity of the Rhodiola preparation) Tyrazole) and its glycoside salidroside (Sidroside) aratikav et al., 1968). Rhodiola has irritating and adaptive characteristics. This compound Objects perform physical work; reduce fatigue; reduce recovery time after prolonged muscular workload And improve the ability to normalize cardiovascular activity. Intensive muscle work In the meantime, Rhodiola optimizes the oxidative phosphorylation process and stabilizes the muscle activity of lipids Improvement of metabolic index (activation of amine acyl-t-RNA-synthetase) in skeletal muscle, R By increasing the NA content and increasing blood supply to muscles, especially the brain, Prevent loss of micurgic phosphate in muscle (Saratikov et al., 1968; Saratik ov, 1974). Rhodiola increases attention, memory; improves mental work; The work performed can be enhanced. The brain regions involved in this activity are the thalamocortical system and And the posterior hypothalamus (Marina et al., 1973). Various other actions are related to Rhodiola And hyperglycemia and hypoglycemia, leukocytosis And the development of leukopenia, erythrocytosis and erythrocytopenia, hypoxemia Stop; including reducing stress and providing a cardioprotective effect. Rhodio The stress-regulating effect of la is normal for its pituitary-adrenal and opioid effects Involved in the transformation. Rhodiola has also been found to increase antitumor resistance in organisms I have. It significantly inhibits the growth of experimental lung ulcers; reduces the frequency of their metastases Prolong the expected life expectancy of animals with chronic tumors and develop sudden tumors. Reduce life (Dementyeva and Yaremenko, 1983). Rhodiola is also neurotic There is some evidence of reducing mortality and fighting extreme fatigue (Saratikov, 1 977).   Salidroside (Rhodiola extract) Salidroside (SAL) is 30mg / kg, animal Prevented disulfiram-induced reduction of NE in the brain. SAL is a member of COMT and MAO. Affects brain NE by its ability to inhibit the activity of. SAL consists of catecholamines and Of the Blood Brain Barrier (BBB) for precursors of serotonin and serotonin SAL does not reduce the properties of the composition and this property Useful in embodiments relating to the treatment of Rhodosin (SAL, aglycone p-ti) Administration of rosole and rosavin (0. 2 mg / kg) in the neocortex DOPA, dopamine (DA), and 5-HT brain levels are increased, and intact The level of NE in the caudate nucleus of the mouse brain decreased, and 30 minutes after subcutaneous injection, SAL was epinephrine. Phosphorus (EPI) and DOPA levels unchanged: at a dose of 30 mg / kg, 26% and% HT, Reduce NE content to 15%; NE, DA and 5-HT concentrations at 100 mg / kg dose respectively Others have shown that this can be reduced to 20, 28 and 23%. L-Dopa to mouse (50m g / kg) and 50 HTP (100 mg / kg) studies have shown that salidroside (30 mg / kg) Exogenous DOPA in animals compared to saline-dopa-5HT-control And serotonin were increased by 26% and 13%, respectively. these The data show that this preparation demonstrates the permeability of the blood-brain barrier for catecholamine precursors. Indicates increased. In addition, a study by Petkov (1981) showed that SAL reduced MOA activity And thus inhibits COMT activity, which indicates O-methylation And catecholamine inactivation by oxidative deamination. Further study Showed that SAL did not alter the activity of% -HTP decarboxylase. That As a result, it does not affect serotonin synthesis from 5-HTP, but slightly inhibits MAO Can slow down the biotransformation of the amine. Obviously, with 5-HTP and SAL In studies involving co-administration of steroids, increased serotonin in the brain was Governed by the latter ability to increase the permeability of the brain barrier.   Literature reveals numerous interactions with Rhodiola and neurotransmitter kinetics ing. In summary, the nucleus accumbens (n. accumben) reduction of dopamine; hypothalamic 5-HT Increased; increased hippocampal NE; and agonist activity of cholinergic receptors reported Have been. Particular mechanisms relate to the different roles of various neurotransmitters in terms of cognition. Has been accepted in neuroscience. The cholinergic mechanism is based on Underlying. The noradrenergic system of the brain enhances positive reinforcement. C The mechanism of rotonin action is more involved in the process of memory merging.   Effects of Rhodiola in rats show activity in negative and positive enhancement It was studied using several methods of avoidance (Petkov et al., (1986)). Negative ( Disciplinary) Using the maze-method in reinforcement, using a maze-method of 0. 10ml simple Rhodiola extract at one dose essentially improves learning and retention after 24 hours Was found. Significant improvement in long-term memory also results from using the same dose of this extract. Established by memory test 10 days after treatment. 0 per rat. In a dose of 10 ml, Rh odiola extract is trained using a "step" method in positive (food) fortification Has a favorable effect on the process. In contrast, the dose used (one rat 0. Other methods using Rhodiola extract at 0. 01ml) have a negative effect on learning and memory And has no substantial effect, which reduces the non-viscous nature of the alcohol-aqueous extract. Show.   White rats showed meclofenoxa in the memory impairment effect of convulsive electric shock. And Rhodiola were used to study the effects (Lazarova et al., 1986). Ten Meclofenoxalate administered intraperitoneally at a dose of 0 mg / kg body weight for 5 days Convulsions during the retention test at 3 and 24 hours after the training session It prevented retrograde amnesia observed after shock. In contrast, for 10 days, 0. Another oral dose of Rhodiola extract at a dose of 10 ml / rat (this is Improved learning and memory with the experimental approach) remained ineffective here .   Huperzine Huperzine is acetylcholine, an important neurotransmitter, or cerebral Has been shown to inhibit enzymes capable of responding to the destruction of It is a compound belonging to a class known as cholinesterase inhibitors. Study It is considered important in learning and memory. Huperzine is a natural occurrence Compound, originally from Huperzine Serrata, a fern of the Lycopodium family Isolated. This is the case in Chinese folk medicine and in recent years Limited interventions performed in China as treatments for age-related memory disorders Used in floor experiments. The result is that Huperzine learns in certain patients And suggest improving memory. However, these suggested results are It has not been demonstrated by floor tests. This natural substance cannot be processed with caution. It is intended for use with the compositions of the substances required in a given patient. In humans, The recommended dose to enhance memory is 150 μg daily (therapeutic range is 1. 50 to 1,500 mcg).   The effect of Huperzine A on scopolamine-induced memory impairment is Radial Maze Task and Choline In Vitro Compared to the Effects of and Tacrine Evaluated using esterase inhibition. Scopolamine (0. 2 mg / kg) Intermittent memory was severely impaired. Huperzine A (0. 1-0. 4mg / kg (by mouth (oral))) , E2020 (0. 5-1. 0 mg / kg, po) and tacrine (1. 0-2. 0 mg / kg, oral) These scopolamine-induced memory deficits can be restored. The color determined by the colorimetric method Tyrylcholinesterase: Huperzine for acetylcholinesterase The ratio of A, E2020, and tacrine is 884, respectively. 57, 489. 05 and 0. Was 80 . This result indicates that Huperzine A is the most selective acetylcholinesterase inhibitor. Bitter, and to scopolamine much better than E2020 or Tacrine Ameliorates the induced working memory deficits, indicating that Huperzine A May be a promising drug for medical treatment of cognitive impairment in Alzheimer's disease patients (Cheng et al., 1996).   Huperzine A, a novel, important, reversible, and selective acetyl Phosphoesterase (AChE) inhibitors are currently in memory for patients with Alzheimer's disease It is believed that it is superior to other AChE inhibitors for treating defects. The effect of Huperzine A on the behavior of rats treated with AF64A in a radial maze was evaluated. (Zhi et al., 1995). AF64A (2 mmol per side in the ventricle) is rat Caused significant deficits in their ability to perform spatial working memory tasks. Of this action Deficiency is marked by choline acetyltransferase (ChAT) activity in the hippocampus Was evaluated with a decline. Huperzine A (0. 4-0. 5mg kg^-1AF64) A-induced memory deficits were significantly reduced. These results indicate that AF64A is It is a useful drug to destroy the working memory process by changing the function, And suggests that such deficiencies can be effectively alleviated by Huperzine A (Zhi et al., 1995).   Huperazon^TMThe main component of is Hika, which is used to treat Alzheimer's disease. It is a self-extract of Huperzia serrata, a fern of the Genocidae family. Done in China Studies have shown that the active substance Huperzine A in this extract has potential for Alzheimer's disease. It is a promising new treatment. In another study, Huperzine A Excellent acetylcholine with good penetration into the CNS and significant in vivo half-life It indicates that it is an esterase (AChE) inhibitor. Two of the two in China Double-blind clinical trial shows that Huperzine A is safe for long-term treatment of Alzheimer's disease dementia And both are effective. In addition to its activity as an AChE inhibitor Recent findings indicate that Huperzine A has other neuroprotective functions; Inhibits glutamate-induced cytotoxicity in hippocampal and cerebellar neuronal cell cultures Injury; shows that Huperzine A promotes dendritic growth in neuronal cell cultures.   Alzheimer's disease is related to acetylcholine and alcohol for normal activity and viability. Characterized by cetylcholinesterase-dependent neuronal abnormalities and degenerations Attached. These cells, which are located in the basal forebrain nucleus, are also similar to Parkinson's disease. Related to other neurological disorders. Huperzine A is a potent acetylcholinesterase The first drug) and E2020 (approved recently by Eisai Pharmaceuticals) Excellent activity. In addition, Huperzine A is used to Protects cells from death caused by excitatory amino and glutamate It has been shown. Due to the two-stage pharmacological action of Huperzine A, Huperazon^{T M} Offers unique and important activity for the treatment of attention deficit and senile memory deficit . Huperzine A toxicity and efficacy studies have shown that Huperzine A has a human therapeutic dose of 50- It shows no toxicity even at 100 times administration. This extract has significant side effects It is active for 6 hours at a dose of 2 μg / kg without use.   A double-blind control study of more than 160 patients in Alzheimer's disease Weschler scale binding at a dose of only 150 μg (given twice daily) (3-5 μg / kg) The results showed a significant improvement measured. Compare Huperzine A with placebo Eleven patients on placebo were compared with Huperzine A by 26 Reported significant improvement in headedness compared to 8 patients and 8 in placebo Patients showed improved memory compared to 16 patients with Huperzine A, and 1 One patient showed significant improvement compared to eight patients with Huperzine A.   Comparing memory improvement between Huperzine A patients and piracetam patients, 50% of Setam patients have improved memory compared to 85% of Huperzine A patients, 30% of piracetam patients were significantly improved compared to 70% of Huperzine A patients Hupe, while 50% of piracetam patients showed no improvement Only 15% of rzine patients showed no memory improvement. As well as other experimental compounds under development. Huperzine A, brain acetyl Very specific about cholinesterase (AChE) versus AChE found elsewhere in the body It is strange. This selectivity may be due to the relatively low toxicity of the extract. Unlike Huperzine A, side effects like muscarinic receptors M1 and M2 Did not bind to receptors in the CNS that could cause Better than stigmine (30 minutes). Behavior of learning and memory enhancement in animals In research, the amount of extract effective for memory and learning and the effective non-toxic dose From the original) were 30- to 100-fold. Huperzine A collects these data. Strongly suggests that it may be useful in treating Ruzheimer's disease with minimal side effects Hinting.   Chromium salts (eg picolinate, nicotinate, etc.). Dietary chrome is required Nutrition, and its value in human nutrition is well established. chromium Is an essential trace mineral and is a cofactor for insulin For the purpose of chromium, which arises from this point of view, chromium does not contribute to insulin action. Plays a role in glucose, lipid, and amino acid metabolism I can do it. The rationale for this argument is that chromium deficiency is associated with defective glucose tolerance, Causes insulin resistance, increased blood glucose levels, and diabetes type 11 symptoms In addition, an appropriate amount of the physiologically active form of chromium May reduce the insulin requirement in the animal (Kaats et al., 1996).   The National Academy of Sciences classifies chromium as an essential trace mineral And recommends taking 50-200 μg daily. But the most reliable Studies show that Americans (as well as others) have suboptimal intakes-the lowest Only 40% and 60% in men report it. Glucose, in Improve insulin and lipid levels; live at home with defective glucose tolerance Subjects; adults with increased cholesterol levels; insulin More than 25 people who demonstrate beneficial effects of supplemental chromium on and hypoglycemic patients There are studies on humans (Mertz, 1992).   In order to increase the bioavailability of chromium, naturally occurring birds Several studies have suggested picolinate acid, a metabolic derivative of putphan. Is being planned. Picolinate acid is combined with trace metal ions in the gut and blood. And promote the collection and use of essential trace metals (Evans and Bowma n, 1992).   Since body fat deposition is thought to be partially regulated by insulin, Improvements in insulin utilization should lead to reduced fat deposition. Insi Enhancing the effects of furin may also have a positive effect on muscle tissue. why If so, insulin directs the amino acid into the muscle cell; Upon entry into the cell, they are located on the cell's genetic material (ie, DNA and ribonucleic acids). This is because they are assembled into proteins through the effect of insulin. Vaniri Reduces competition for amino acids such as amino acids or leucine, thereby This effect of chromium is important for the present invention because it allows for an increase in the amount of putophane. It is important (Wurtman, 1982). Insulin can also be used to build an organization Disruption or catabolism of body proteins that have a net effect on increasing active proteins Is shown. Chromium can potentially help maintain or add fat-free mass (FFM). C If rP can reduce insulin resistance, it has been suggested that it can improve body composition I have. Because insulin resistance or deficiency is associated with glucose and amino acid Impairs entry into muscle cells and catabolism of muscle proteins as well as insulin Increases the likelihood of protein deficiency and promotes lipid deposition (Kaates et al., 1996). Other references indicate that insulin resistance, despite the level of obesity, Works like a “set point” to prevent weight gain Can help stabilize body fat in E. coli (Eckel, 1992). In general, animals Studies support this claim (Liarn et al., 1993), but one study in humans showed that CrP Changes were found in body composition with supplementation of sulphide (Hasten et al., 1992) In another, there was no statistically significant change in body composition but a positive Reported (Hallmark et al., 1993), and in the third, using CrP supplementation Did not find any positive changes in body composition (Clancey et al. , 1994). The controversial nature of the literature is that most human studies have shown a small The subject is used, and the subject often follows an exercise or conditioning program. This may increase the need for chromium in amounts greater than those provided in these studies. Make things clear.   Earlier studies in which concomitant use of chromium recruitment and exercise were observed were competing. Have limited the effects of weight and body composition (Clancy et al., 1994; Evan s et al., 1989; Evans et al., 1993; Hallmark et al., 1996; Hasten et al., 1992).   Chromium picolinate is the most commonly used, studied and promoted chromium compound. In vivo studies have shown that chromium nicotinate also reduces body weight in body composition. Suggests that it may be feasible in areas of low and change. In this regard, In a very recent study by the authors, nicotinate was even better than picolinate. Suggest that it may be more important (Grant et al., 1997). This data is Nicotinic acid upon addition of the substance specified in the preferred embodiment to the basic composition An example of the usefulness of chromium is provided herein.   Pharmaceutical composition. The aqueous compositions of the invention are disclosed for treating RDS-related disorders. Effective amounts of various compounds, including a pharmaceutically acceptable carrier or water. Dissolved or dispersed in sexual media, including obesity, ADHD, Tourette's syndrome, PM S, smoking, and any other relevant behaviors described herein. The phrase “pharmaceutically or pharmacologically acceptable” should be appropriately invested in animals or humans. Molecules that do not produce harmful, allergic or other adverse reactions when given Represents elements and compositions.   As used herein, "pharmaceutically acceptable carrier" refers to any And all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and Including absorption delaying agents. Such media and agents for pharmaceutically active substances The use of is well known in the art. The active ingredient can be any conventional vehicle or agent. Except where otherwise indicated, its use in therapeutic compositions is contemplated. Supplementary The active ingredient may also be incorporated into a composition. Preparations for human administration Is sterile, pyrogenic, and general as required by the FDA Office of Biologics standards. It should be compatible with standard stability and standard purity.   Biological materials can be extensively removed, where appropriate, to remove unwanted small molecular weight molecules. For formulations that are dialyzed into and / or ready for the desired vehicle Should be lyophilized. The active substance is then generally processed for parenteral administration. (Eg, via intravenous, intramuscular, subcutaneous, intralesional, or even intraperitoneal routes) Prescribed for injection). Preparation of an Aqueous Composition Containing Active Components or Ingredients Are known to those skilled in the art in light of the present disclosure. Typically, such a composition is For injection, they may be prepared as either liquid solutions or suspensions; Solid forms suitable for use in preparing solutions or suspensions by addition Can also be prepared; and the preparation can also be emulsified.   Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; Commodities include sesame oil, peanut oil or aqueous propylene glycol; Sterile powder for the extemporaneous preparation of sterile injectable solutions or dispersion. All places In this case, this form needs to be sterilized and can be easily used with a syringe It needs to be fluid to some extent. It is stable under manufacturing and storage conditions Must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Need to be done.   Solutions of the active compounds as free bases or pharmacologically acceptable salts are prepared at the interface Formulation in water properly mixed with an activator (eg, hydroxypropylcellulose) Can be made. Dispersions also include glycerol, liquid polyethylene glycols, and And in mixtures thereof and in oils. Normal Articles of Preservation and Use In some cases, these preparations contain a preservative to prevent the growth of microorganisms .   A compound for the treatment of an RDS-related disorder of the present invention may be a composition in a neutral or salt form. May be prescribed. Pharmaceutically acceptable salts include acid addition salts (free amino acids of proteins). And formed with an inorganic acid, such as hydrochloric acid or Phosphoric acid) or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. Formed. Salts formed with the free carboxyl groups also include inorganic bases. (E.g., sodium, potassium, ammonium, calcium, or Diiron) and organic bases (eg, isopropylamine, trimethylamine, hiss) Thidin, procaine, etc.). Peptide therapeutics as active ingredients U.S. Patent No.4,60, each of which is hereby incorporated by reference for its use. 8,251; 4,601,903; 4,599,231; 4,599,230; 4,596,79 No. 2; and 4,578,770 may be used.   The carrier can also be a solvent or dispersion medium; for example, water, ethanol, Riol, (eg, glycerol, propylene glycol, and liquid polye Ethylene glycol, etc.), suitable mixtures thereof, as well as vegetable oils. An example For example, the use of coatings such as lecithin may Proper flow by maintaining a controlled particle size and by using surfactants. Mobility can be maintained. Prevention of the action of microorganisms is on a variety of antibacterial and antifungal agents (eg, For example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, Etc.). In many cases, isotonic agents (eg, sugar or (Sodium chloride). Extended absorption of the injectable composition Of drugs that delay the release (eg, aluminum monostearate and gelatin) It can be brought about by use in a product.   Sterile injectable solutions contain the active compound in the required amount in an amount of various other ingredients enumerated above. Prepared by incorporation in a suitable solvent having Sterile filtered. Generally, dispersions are a mixture of various sterilized active ingredients in a basic dispersion. A sterile vehicle containing the vehicle and other ingredients required from those enumerated above Prepared by incorporation. Of sterile powder for the preparation of sterile injectable solutions In some cases, the preferred methods of preparation are vacuum drying and freeze drying techniques, which are From its pre-sterilized filtered solution, the active ingredient and any further desired This produces a powder of the ingredients. Preparation of more or more concentrated solutions for direct injection Is also contemplated, where the use of DMSO as a solvent is It is expected to result in rapid penetration, high concentration delivery.   Upon formulation, solutions will be in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. Is administered. The formulations may be presented in various dosage forms, such as the type of solution for injection described above. Although easily administered, drug release capsules and the like can also be used.   For parenteral administration of aqueous solutions, for example, solutions may be suitably buffered if necessary. Liquid diluent should first provide sufficient saline or glucose Used to provide isotonicity. For intravenous, intramuscular, subcutaneous and intraperitoneal administration, These particular aqueous solutions are particularly suitable. In this connection, sterilization can be used Aqueous media are known to those of skill in the art in light of the present disclosure. For example, 1 dose is 1 ml Can be dissolved in isotonic NaCl solution and added to 1000 ml subcutaneous infusion fluid or Either injected at the proposed site of injection (eg, "Remlngton ' s Pharmaceutical Sciences, 15th Edition, pp. 1035-1038 and pp. 1570-1580. Thing). Depending on the condition of the subject being treated, the dosage will necessarily vary somewhat. Move. In any case, the person responsible for administration should be Determine the amount.   The active agents described herein may range from about 0.0001 to 1.0 mg per dose. Regram, or about 0.001 to 0.1 milligram, or about 0.1 to 1.0 or more It may be formulated in a therapeutic mixture to contain about 10 milligrams. Multiple doses also Can be administered.   In addition to compounds formulated for parenteral administration, such as intravenous or intramuscular injection Other pharmaceutically acceptable forms include, for example, tablets or other solid forms for oral administration. Currently used including body; liposome formulations; time release capsules; and creams Including any other forms that have been implemented.   Nasal solutions or sprays, aerosols or inhalants of the present invention may also be used. You. Nasal solutions are usually designed for nasal passage in droplets or spray It is the aqueous solution. Much of the nasal secretion is the same, and normal ciliary action is maintained. A nasal solution is prepared. Therefore, nasal aqueous solutions are usually isotonic And slightly buffered to maintain a pH of 5.5 to 6.5. Furthermore, for eyes Antimicrobial preservatives similar to those used in the preparation and, if necessary, suitable drug stabilizers May be included in the formulation. Various commercial nasal preparations are known and include, for example, antibiotics. Contains substances and antihistamines and is used for the prevention of asthma.   Further formulations suitable for other modes of administration include vaginal suppositories and vaginal suppositories. No. Rectal vaginal suppositories or suppositories may also be used. Suppositories come in a variety of weights and shapes A solid dosage form, usually mediated for insertion into the rectum, vagina, or urethra It is. After insertion, the suppository softens, melts or dissolves in the cavity fluid. In general, suppositories Traditional binders and carriers (eg, polyalkylene glycols or Or triglycerides); such suppositories may comprise from 0.5% to 10%, preferably May be formed from mixtures containing the active ingredient in the range of 1% to 2%.   Oral formulations may contain commonly used excipients such as pharmaceutical grades of mannitol, Lactose, starch, magnesium stearate, sodium saccharin, Lulose, magnesium carboxylate, etc.). These compositions comprise a solution, It takes the form of a suspension, tablet, pill, capsule, sustained release formulation or powder. Special In certain defined embodiments, the oral pharmaceutical composition is an inert diluent or anabolic A gelatin capsule containing a workable edible carrier or containing hard or soft shells. Can be encapsulated in tablets, compressed in tablets, or Can be directly incorporated. Active compound incorporated into excipients for oral therapeutic administration Tablets, buccal tablets, troches, capsules, elixirs , Syrups, wafers, and the like. Such composition Preparations and preparations should contain at least 0.1% of active compound. Composition And the percentage of preparation can, of course, be varied and, conveniently, the unit of It may be between about 2 and about 75% by weight, or preferably between 25-60%. This The amount of active compound in the composition useful for the treatment of such .   Tablets, troches, pills, capsules, and the like can also include: a binder (eg, , Tragacanth gum, acacia, corn starch, or gelatin); For example, dicalcium phosphate); a disintegrant (for example, corn starch, potato Lubricants (eg, magnesium stearate); And a sweetener such as sucrose, lactose or saccharin may be added. Or flavorings (eg peppermint, wintergreen) Il, or cherry flavoring). When the dosage unit form is a capsule, Liquid carriers may be included in addition to materials of the type described above. As coating Otherwise, various other substances exist to modify the physical form of the dosage unit. obtain. For example, tablets, pills, or capsules may be made with shellac, sugar or both. Can be Elixir syrup is used as an active compound and as a sweetener. Sucrose, methyl and propyl parabens as preservatives, pigments and cherries Or perfume such as orange perfume.   kit. Therapeutic kits of the present invention are of the present invention for the treatment of RDS and related behaviors. A kit comprising one or more agents or compounds described in the specification. like this The kit will generally include, in a suitable container means, any pre-formulated pharmaceutically acceptable formulation. And the pharmaceutically acceptable formulations described above. The kit may have a single container means Or it may have a separate container for each compound.   Where the kit compounds are provided in one or more liquid solutions, the liquid solutions may be aqueous. Liquid, sterile aqueous solutions being particularly preferred. Compounds for the treatment of RDS-related disorders Also, it can be formulated into a syringeable composition. In this case, the container means itself It can be a syringe, pipette, or other such device from which the formulation can be Can be applied to an area, injected into an animal, or further adapted to other components of the kit. Used and mixed.   However, the components of the kit may be provided as a dry powder. Reagent or component Is provided as a dry powder, this powder can be reconstituted by the addition of a suitable solvent. Can be done. It is envisioned that the solvent may also be provided in another container means.   The following examples are included to demonstrate preferred embodiments of the invention. Example The techniques disclosed therein are described below in order to work well in the practice of the present invention. Represents the technology disclosed by the inventors, and is therefore preferred in its practice. It should be appreciated by those skilled in the art that But However, one of ordinary skill in the art will appreciate the disclosure and further similarity in light of the present disclosure. Are specific embodiments that achieve similar results and depart from the spirit and scope of the invention. It should be understood that many changes can be made without having to do so.                                 Example 1        Amino acid load and enkephalinase inhibition in familial overeating Introduction   We consider that RDS is a response to one or more neurotransmitter deficiencies. I can. Attempts to reduce this neurotransmitter imbalance due to drug receptor activation, It only substitutes for the lack of reward, and is merely a temporary It only creates a sense of focus. From this point of view, we consider uncontrolled intake behavior Recovery from a particular form of (i.e., SUD) Designed to reverse brain deficiency from administration of both inhibitors (Blum et al., 1988a; Blur). m et al., 1988b; Brown et al., 1990). We consider amino acid precursor loading and enke Farinase inhibition maintains weight loss in an outpatient setting over a two-year period It was decided to evaluate the question of whether it could be increased. Method   Subject selection and program. Subjects in this study were Sacramento, California Supplemented by a fasting program at a Behavioral Medicine Group Clinic, There were 247 outpatients with very low calories. The subjects are Ensure that the patient does not continue fasting until within 15% of their target weight or Optifast as a nutritional fasting product until you choose^TMWas used. The present inventors have Other diet regimens formulated with care are Optifast^TMActs instead of Expect to be able to. Standard Metropolitan Life Insurance height / weight chart Use to determine ideal body weight. All subjects received Centrum vitamins during the entire study. I took a kind. Each subject will give informed consent and Le from the San Antonio Institutional Review Board under the protocol for obesity research Behavioral Medicine Medical Group Clinic Institutional Review Co. Approved by mmittee and the University of Texas Health Science Center.   Patient is PHENCAL^TMThe decision to get or not was made at the end of the fast. Highest Have a high feeding score, and sweeteners (sweetener), bread, citrus fruits, pasta, etc. Tomorrow about the most difficult time to withstand certain carbohydrates such as Difficult to lose weight, or even reach their target weight Patients were considered to be more difficult to treat. About most Patients complaining or those whose eating was uncontrolled were selected and PHEN CAL^TMWas taken (study group; N = 130). If maintenance seems easy, then For patients, PHENCAL^TMWas not provided (control group; N = 117). PHENCAL for selected subjects^TMTreatment started at the end of the fast and 2 Continued during the maintenance period until the end of the year study. PHENCAL^TMIs an amino acid and Vitamin supplement, 1899 Limited Liability Corporation (San Antonio, Te xas) designed, developed and manufactured by Weider Nutrition Gro PHENCAL marketed by up (Salt Lake City, Utah)^TMIt is a pioneer. Selected Patients received 6 capsules per day of PHENCAL^TMTake 460mg DL-Fe Nylalanine, 25 mg L-tryptophan, 25 mg L-glutamine, and 5 mg Lidoxal 5'-phosphate, 33 μg chromium picolinate, and 10 mg L-carni Consists of chin.   Patients weighed once a week before and after attending educational classes. Each patient Attendance classes were attended by the medical director of the program and a registered diet Educated by the lawyer, it is a disease of obesity, its epidemic in society, Prevention, its impact on personal health and well-being, its treatment, the role of the family, Possible genetic disorders, use of nutritional supplements, role of proper nutrition in eating, diet The concept of high protein, low fat and very low or no carbohydrates, the role of exercise in Was configured to include. In addition to their mental state, medical conditions are monitored weekly. I was negated. Mental status is an assessment scale for food cravings, sullenness and gluttony. Was monitored as a score for the rule. Craving and fool eating are 1-5 Recorded in Kale. A score of 5 on the covet scale indicates emotions and completely out of control. And showed unpleasant feeding. Score 1 indicates that even if an individual Follows, even when you know you're happy and not physiologically coveted Showed desire. Grumpy was rated on a similar scale, with 5 being very sullen and 1 Has the least mood. Fool eating is more than enough points per week Recorded as number of episodes. Laboratory analysis of blood is performed every other week, while Urine analysis provided information about medical status. Chemical panel for blood And SMAC-CBC, while urine is mainly composed of ketones and / or Source was analyzed. Education classes were one hour per week. Weight loss Nutrition, exercise, behavioral changes, and stress tubes to support low and long-term maintenance He emphasized the principle of reason. Characterization of the subject population. Of the 247 subjects, 84% were female. Everything All subjects were Caucasian and the average age was 40 years. average Typical subjects were 74% overweight when participating in the program.   PHENCAL^TMThirty-one study subjects who were taken had age, ideal weight, starting weight, overweight 117 individuals with% excess weight, longing, sullen period, overeating, or obese family history Control subjects were not significantly different (see Table 20-B). But They differed in the family history of drug dependence (CD +). Study group subjects 65% had a family history of drug dependence (CD +), while control subjects Were CD + (p <0.005). Subjects complained that they were more complaining If there is a loss of control during weight maintenance, or Selected, these data indicate that CD + subjects are more complaining and maintain weight Indicates that they seemed to have more difficult time during the period.Subject characteristics. Numbers are expressed as mean values. Excess weight% = [starting weight-ideal weight] / Ideal weight; OB% =% of groups reporting a family history of obesity; CD% = Drug dependent % Of groups reporting family history. Phencal^TMIs the 1899 Limited Liability Corpor ation, San Antonio, Texas and Weider Nutrition Inc., Salt Lake City, Ut ah product. Gender differences. 208 women in study average 76% excess at start He was overweight, while 39 men were 66% overweight. Standa The ideal weight was determined using the rd Metropolitan Life Insurance height / weight table. Man Almost three-quarters (73%) of women are morbidly obese compared to about half (49%) of their gender. (Ie, over 50% overweight). Women are five times more likely than men in this program It was a group that excelled at the top. Over 90% in this study during intake interviews Women report food cravings, while slightly less than 80% Hope reported. The occurrence of gluttony was also significantly different between men and women. Male 6 80% of women reported fool eating, compared to only 4%. Family aspects of the patient. Upon participation in the program, each subject should have a family history of obesity and medication. She was asked about her family history of dependence. Slightly more than 70% women, and 56 % Of men reported a family history of obesity. Of those with a family history of obesity, About twice as many subjects reported having an obese mother (73%) compared to their father (38%). Was. 11% of these with a family history of obesity reported obesity in their parents. Women and Almost half of both men reported a family history of drug dependence. But in this case, the trait It was my father who held 31% of mothers with a family history of drug dependence 86% all compared that their father was drug-addicted reported. About 2/3 (63%) of morbidly obese (over 50% overweight) subjects are obese Report that they have a mother who has been I told. Men account for only 16% of the total population, so the family history subgroup Any statements regarding are at best preliminary. result   Maintain weight loss. 247 subjects averaged over an average of 20.0 weeks of fasting Lost 68.4 pounds. The study group decided to end fasting, and PHENCAL^TMThe start of the Although previously different from the control group, this difference was not significant. the study Group is overweight at the end of fasting, 32% of control group 22% overweight. Despite this difference, the statistical analysis Body weight at end of fasting showed no effect on weight loss at 2 years . At the end of two years of research, PHENCAL^TMSubjects taking PHENCAL^TMCon On average 23.5% excess weight compared to 52.8% in the trawl group (P <0.0001) [see FIG. 2]. Two years later, subjects in the study group Compared to 41.7% of control subjects who regained their lost weight Recovered only 14.7% of their lost weight (p <0.0001) .   Genetic effects. Comparison between study and control subjects by family history (OB + / CD +, OB + / CD-, OB- / CD +, and OB- / CD- groups), PHENCA L^TMAll groups taking two years from any control subgroup There was less excess weight (p <0.0001). In this example, OB is not a gene, So This is a family history of obesity. All groups with a history of OB +, two years later, There was excess weight over comparable OB-groups (p <0.05). Statistically significant Patients with no family history of drug dependence^TMResponded well.   Genetics and gender. In general, all male family history groups are comparable to women. Less weight was regained dramatically than the control group (p <0.0001). In the best case ( OB- / CD +), men at the end of two years have virtually lost the weight lost during fasting. I didn't go back. In this study, women are more than five times as many as men, By contrast, women differ from men in some characteristics, and we therefore further characterize women. I decided to charge. 70% of women report a family history of OB +, while 54% Reported a family history of OB +. Report a family example that is neither CD- nor OB- Only 12% reported. Women who had OB + and CD + had OB- On average, they were 58% heavier than women with / CD-. In addition, OB + / CD + women Was the most overweight: followed by OB + / CD-, then OB- / CD + OB- / CD- women had the least excess weight. Similar progress but food crave , Fool eating, eating and sullen scores. OB + / CD + women Reported the most coveted, ridiculous, and sullen.   Food preference and gluttony. The patient's mental status and medical condition were monitored. Mental state The situation is qualitatively monitored for the food craving, sullen, and glut eating scales. I started A five-point scale was used for food cravings. On the coveted scale A score of 5 indicates emotions completely out of control and eating past discomfort: score 1 Even if the individual does not agree that he or she is satisfied and physiologically covets Even when he knew, he showed a lingering desire. Grumpy on a similar scale Rated 5 is very sullen and 1 is the least sullen. Fool eating a week It was recorded as the number of episodes of feeding past the sufficient points per hour. Experiment Compliance with the regimen was assessed by questions.   At the end of research, PHENCAL^TMSubjects who took the test compared to the control group The craving was reduced by a factor of 3 (at least p <0.0001); K Did not decrease. Number of fool-eating episodes is PHENCAL^TMCont that did not take PHENCAL compared to roll^TMThere was a significant decrease in subjects who took the test. Participation in research At that time, the subject reported 10.9 fool eating episodes per week. At the end of the study, subjects had only 2.9 fool-eating episodes per week Just reported. In contrast, non-PHENCAL^TMConte The roll group reported 8.3 episodes per week. Research In addition, the control group received 8.3 ridiculous episodes per week Reported, indicating no significant change. Two years later, longing for food and Both fool eating are PHENCAL compared to the control group^TMGlue Three-fold.   Multiple regression and analysis of variance. After the start of the treatment program using stepwise multiple regression The significance of the predictor variable of weight percent returned at 2 years was tested. The predictor variables are none (0) or Yes, divided into categories as (1), and whether the patient is morbidly obese or not, Whether or not they are easy to craving, whether or not they have a family history of drug dependence, obesity Whether they have a family history, whether they are women, and PHENCAL^TMIs administered Or not. Stepwise selection procedure (SPSS Version 6.13, (SPSS, Inc., Chicago , IL)) are PHENCAL as significant predictors of weight gain at 2 years^TMProcessing, women, Morbid obesity and a family history of obesity were selected. Fool eating, coveting, and medicine Property-dependent family history was not statistically significant as a predictor variable. Selected forecast The overall model of the variable is 39.8% with a two-year weight gain explained by the predictor variable Was significant (p <0.0001). The predictor variables that have the most effect on the set of predictor variables Number is PHENCAL^TMFollowed by a family history of morbid obesity, women and obesity (Table 20-C See). In the second analysis, PHENCAL^TMGroups and Control Centrum Guru The fool-eating scores before and after the two-year period with the group were compared. PHENCAL^TMTreatment group Two-factor variance between the loop factor and repeated measures of fool eating scores around two years Analysis found a significant interaction (p <0.001). Uses two-tailed t-test Then, about the change in fool eating score, PHENCAL^TMGroups and controls Were tested separately. Statistically, the control group The changes that can be made Did not, PHENCAL^TMDramatic changes in fool eating for groups Decreased. Debate   The data presented in the open pilot study for the past two years is based on the neuronutrient PHENCAL^TMBut, Weight loss while suppressing abnormal intake behavior in known carbohydrate frenzy Suggest to prevent return. The present inventors, PHENCAL^TMObvious beneficial effects of Are precursor amino acids and enkephalins that act on the central limbic reward circuit It is believed that both effects of inhibition can be explained. We have at this time It cannot provide the exact mechanism of action of the neurotrophic mixture, and we have Ingredients or Combination of Ingredients Most Prevent Carbohydrate Flea Eating in Chinese Studies Cannot be specified.   Neurotransmitters 5-HT, DA, NE and enkephalins reduce sweet food intake (Leibowitz, 1985; Leibowitz et al., 1982; Kaye et al., 198 4; Riviere et al., 1987; Blum et al., 1990). Therefore, PHENCAL^TMIs 1-tryptophan Precursor amino containing ethane (5-HT precursor), 1-phenylalanine (DA and NE precursor) Enkephalinase inhibitor d-, which increases acid load and enkephalins Phenylalanine (Blum et al., 1986) increases these food-inhibiting neurotransmitters Specially designed to do. PHENCAL in these studies^TMOf the observed effect of The corresponding positive mechanism is that defective monoamines such as 5-HT, NE, and EPI And recovery of neuropeptides met-enkephalin and CCK-8. These Be Are considered to be food or carbohydrate substances that are affected by glucose or genetics. (Frohman, 1983; Fullerton et al., 1985; Matsumura et al., 1984).   PHENCAL^TMAre men with the same family history as women with OB + and CD + It is noteworthy that it induced its greatest effect as compared to. This difference Shows human obesity (OB) and human dopamine D2 (DRD2) Both genetic variants of the offspring account for up to 22.8% of the variance in the Body Mass Index (BMI). May be relevant to the recent findings of Comings et al. (1996b) who observed that obesity In view of the interaction between OB and DRD2 gene in Leptin binding to leptin may be involved. This coupling is important for behavior and appetite and Activates intermediate neurotransmitters or neuropeptides that have an effect on metabolism . In this regard, Ob / ob mice have also become arcuate-infundibullum Is known to have significantly reduced levels of dopamine (Oltmans, 1983). On the basis of this work, we have developed glucose as previously proposed. Binding is similar to other drug dependences (i.e., alcohol, cocaine, heroin). I think that.   2 years, non-PHENCAL^TMPHENCAL compared to the / Centrum vitamin group^TMAmi The groups taking the acid-free regimen: 1) In% of excess weight for both men and women 2 fold reduction; 2) 70% reduction in craving for women and 63 for men % Reduction; 3) 66% reduction in large meals for women and 41% for men Decreased.                                 Example 2         Correlation of VNTR alleles with Tourette syndrome and substance abuse   TS is used for chronic motor and vocal tics and a wide range of related behaviors (Alcohol Drug and substance abuse, depression, and obsessive-compulsiveness, intentional hyperactivity, behavior, sleep, Complex neuropsychiatric disorders characterized by learning, sexual and anxiety disorders) (Comings and Comings, 1987c, Comings, 1990, Comings and Comin gs, 1993, Comings, 1995d). TS is usually received as the autosomal dominant trait Gts. Although it is assumed that they are inherited (Comings et al., 1984, Pauls and Leckman, 1986), Linkage studies have virtually eliminated the entire genome without finding the Gts gene (Fog, 198 5; Tsui, 1994). However, a highly significant increase in behavior, and Gts and A Refractory disease with increased gene load for the DHD gene has recently been shown (Co mings, 1995a). Studies of transmissible offspring of Tourette's syndrome suggest that this disease May be polygenic if lifetime risk is not less than 12 per 1,000 (Comings et al., 1984). The TS for school-aged boys is 1 out of 90 complete TS The frequency, and frequency of 1 in 40, probably TS (Comings et al., 1990). same Results have been observed in other studies (Kurlan et al., 1994), and The frequency of TS or chronic ticks in rats was determined to be 2.6% (Zohar et al., 1992). More recent offspring studies include the full spectrum of TS-related behavior (Comings, 1990 , Comings, 1995d), many families find that these genes are Provide evidence that has been inherited, and it has been discussed that TS is a polygenic disease. (Comings, 1990; Comings and Comings, 1992; Comings, 1994b; Coming s, 1995b; Kurlan et al., 1994).   Broad spectrum of related diseases, and Gts gene being inherited from parents For evidence (Kurlan et al., 1994; Comings, 1990), TS is a polygenic disease, Moreover, these genes (MAOACX, DBH, DRD2, DATI, etc.) Pamine, serotonin, norepinephrine and other neurotransmitters Offspring were shown to be involved, contributing only 1 to 10% of the variability (Comings, 1996 b; Comings, 1995a, Comings, 1995b; Comings, 1996a). Method   Group I: TS group. Subjects consisted of 57 controls and 229 TS probands (Comings 1990), most of whom had severe multiple related behavioral disorders, And the relatives of 90 perverted or nonperverted TS probands . All subjects were non-Spanish whites. The average age of the subjects, Types (TS vs. chronic motor tics) and other aspects are described elsewhere (Com ings et al., 1996a).   Behavioral score. Each TS control and TS proband or relative should be Based on Interview Schedule (Robins et al., 1981) or DSM-III-R (1987) criteria Was asked to fill out a questionnaire. It is built of extensive psychiatric symptoms Provided a review. These symptoms include ADHD, substance abuse, mood, anxiety, Grouped into 27 different actions including movement, stuttering, tic and others . The questions used for these behavioral scores are the others (Comings 1995a; Comi ngs 1994a, Comings 1994b; Comings 1995b; Comings et al. 1996a; Robins et al. 1981; C omings 1995c). ADHD using two behavioral scores evaluated. The first is called ADHD and is based on the DSM-III and DSM-III-R standards. Based on the presence of at least half of a series of 22 ADHD variables from Second ADHD-R was based on the DSM-III-R diagnostic criteria. Three that have not been used earlier QTVs were casual, impulsive and hyperactive. These are ADHD There were three sub-scores that produced cumulatively. The abbreviation for QTV is condu ct) CD for disease, ODD for refractory disease (Comings 1995a), and Includes episodes of depression (Comings 1995c).   The rationale for examining co-morbid behavior is that specific genes are more likely to Earlier observations may strongly correlate with specific co-morbid behaviors present in , 1996a). This question should provide a DSM-III-R or DSM-IV diagnosis Highly constructed method of generating QTV for different areas of behavior without implying Means to provide. The advantage of continuous traits is that they Is to provide a large range of rigor. A questionnaire based on the questionnaire The accuracy, usefulness and sensitivity of the approach are more than others (Gadow and Sprafkin 1994 ; Grayson and Carlson 1991), the use of such tools has been Demonstrated by comparison with the treatment of the contactor. Questions with hundreds of subjects Reviewing the sections, they should accurately reflect the information obtained from personal interviews. Was shown.   Group II: substance abuse group. Patients from 120 non-Spanish white men Configured.   Evaluation. All subjects had a 24 item personality revised to include substance abuse Michigan Alcoholism Severity Test of questions (Davis et al., 1987) (MAST-R), Diagnostic Interview Sch by clinicians to diagnose the presence of drug-dependent diseases edule (DSM-III-R version) (Robins et al., 1981), and alcohol and drug use Clinicians' Addiction Severity Index Fifth Editi to evaluate number ranges On (Hodgins and Guebalyl992) (ASI) was used to evaluate.   We utilize the ASI DRUG / ALCOHOL USE and LEGAL STATUS sections did. Lifetime alcohol use (years), poisoning, Loin, other opiates / analgesics, barbiturates, other sedatives / hypnotics / mental For use in fixed doses, cocaine, amphetamine, cannabis, hallucinogens, and inhalants A question was asked about. For each of the above, if relevant, And questioned the subject. Options are oral, nasal, smoking, and intravenous. Was. Continuous variable #IV drug used sums the total number of different drugs injected intravenously (IV) It was calculated by Variable IV drug use is 0 for no IV drug use and one or more ≤1 dichotomous variable for drug IV. If you have questions about drug issues, "How many times have you had alcohol DT? Overdose?" "Last 30 How many days in a day do you have alcohol problems? , Drug problem? Did you experience the past 3 Are you alcohol during day 0? Drug? How much did you spend on it? " . The question also asked about various legal aspects of drug and alcohol abuse. " How many times in your life have you been arrested and reproved for a charge? "This How many of these charges have been convicted? And so on. Response from 0 to any If they were in the range of numbers, they would be "0" for 0, and any other number. The score was scored as "1". These questions related to alcohol use, Questions summed about total alcohol score and related to drug use The scores were summed. Interviewer-based alcohol and / or substance abuse The severity assessment of the need for treatment is from 0 (no need for treatment) to 9 (life threatening). Need action to intervene in the situation).   Substance abuse control group. Controls for the substance abuse group It was independent of controls for TS patients. They consist of two sets Was. First, 45 non-students from California State University in San Bernardino. An older male Paine Caucasian student (mean age 30.1). With drug abuse Those with significant problems were excluded based on the MAST-R test. The second set The group consisted of twin male parents from the Minnesota Twin Family study. these Is simply to confirm from the overall condition that it had an age of 11 or 17 years. Because they were bitten, they were all socio-economic and educational Represent a more random set of groups. All controls are drug abuse Was scored negative for the drug variables, but the result of the substance abuse assessment was Some were positive because they were not yet available for twin control. Can get. However, this is primarily a random cross-section of a country, We estimate that the number of false negatives in this group is small.   PCR^TMPolymorphism. The MAOA VNTR polymorphism (Hinds et al., 1992) was utilized. This compound polymorphism Gender is associated with alleles that differ in the number of both dinucleotide repeats and VNTR repeats. In turn, the GT immediately adjacent to the novel 23-bp VNTR motif that was incompletely replicated Consists of microsatellite. DNA was extracted from whole blood by standard procedures. The target DNA is PCR^TM(Mullis et al., 1986). PCR^TMLabel the product 0.1 μM of each primer was added to the fluorescent substance HEX or FAM Amidite (Applied B iosystems, Foster City, CA) and used as primers in the reaction (Table 2). 0-D). PCR diluted 10 times^TMDeionize 2 μl of product to 2.5 μl Formamide and 0.5 μl ROX 500 standard (Applied Biosystems, Foster City, Calif.) And denatured at 92 ° C. for 2 minutes and applied to Applied Biosystems Loaded on a 6% polyacrylamide gel in a 373 DNA sequencer. gel Was electrophoresed at 1100 volts and a constant 30 ° W for 5 hours. Scan gel with laser And analyzed using an internal ROX 500 standard. Peak to base pair length Genotyper (version 1.1) based on more sized color fragments (App lied Biosystems). Complete information for each sample can be found in the gel file Data was printed from each time and compiled for analysis.   Allele group. MAOA allele length may correlate with phenotypic effect To test the hypothesis, the alleles were divided into four groups (see results When). These are labeled as shortest to longest 1 to 4, and MAOA genotype variables are Formed. Women were used only in the TS group. Predetermined allele guru Only those that were homozygous for the soup were included in the analysis.   Statistical analysis. ANOVA was used for the Tourette syndrome group, and four different pairs were used. The relative size of each QTV relative to the genic group was determined. Using linear ANOVA, Test for a significantly progressive increase in the mean across the four allele groups Tested. The SPSS (SPSS, Inc., Chicago, IL) statistics package was used. Linear ANOVA Has the subcommand polynomial set to 1. Using MANOVA, all variables are When examined simultaneously, it was determined whether any QTV was significant. Multivariable line All variables were examined simultaneously using shape regression analysis as a second approach At times, it was determined whether any QTV was significant. MAOA genotype, dependent variable And 27 QTVs were entered as process independent variables.   χ2. The above study shows that the group with the longest allele is Showed that it had the highest average. Allele group of 335 bp or less Possible progressive decrease in the frequency of the four progressively fewer TS symptoms Compared across groups: proband with ADHD, TS proband without ADHD , Related persons with TS and relatives without TS.   MANOVA. Four MAOA alleles using MANOVA for the substance abuse group Between the group and the two abstract variables alcohol score and drug score It was determined whether there was a significant association. Using ANOVA, four allele groups The average of alcohol score and drug score was examined for the loop.   Linear χ square. Using this, a possible progressive increase in the frequency of the group below 335 bp Were examined across three groups: control, behavior-free substance abusers (ATU None), and substance abusers with behavior (with ATU). The group without the ATU has this conflict Gene Groups Are Frequent in Drug Abusers Due to Simultaneous Morbidity of Different Behaviors Was included to exclude the possibility that could be increased. Eliminating this The frequency of the allele group may be more It had to be at least 20% higher in users. The hypothesis is that these pairs The frequency of alleles can increase progressively across the three groups. Therefore, linear chi-square statistics were used.   regression analysis. Determine maximum% variance of drug-related variables explained by MAOA gene To perform a regression analysis, which retains alleles of 335 bp or less. Subjects scored as 1 and subjects carrying the 335 allele were scored as 2. And scored. This was performed on drug dependent variables (control = 1, A Without TU was scored 2 and with ATU was scored 3). Because this Is because the chi-square variable was most highly associated with the MAOA gene. result.   Allele group. The distribution of alleles in both groups is shown in FIG. this Were complex VNTRs, so alleles were even or odd base pair clear brackets. Did not enter the pattern. The result is that they are produced by the Genotyper program. Shown exactly as done. There was no allele between 316bp and 323bp This resulted in two distinct major groups <320 and> 320 bp. But the expression To enable testing of the hypothesis that type effects can be related to size, The alleles of the 323-339 bp group were alleles shorter than the main peak 320-333 bp, 33 3 subgroups consisting of a 4bp main peak and alleles longer than the main peak of 335bp or more Divided into loops. 219 subjects for a total of 375 subjects in the TS group Males and 156 females. Of the women, 88 are heterozygous there were. If these were excluded, it would leave 287 subjects in the study, 36 of them are controls. In this final group, men vs women There were no significant differences in the frequency distribution of the four allele groups.   TS group. ANOVA results for each of the QTV versus the four allele groups The results are shown in Table 20-D. The results for formal ANOVA are shown below the F ratio and p-value. The F ratio for a linear ANOVA is_TwoBelow the column, for values that were significant at <0.05 Shown with superscript 1. QTV is F_TwoAs the F ratio in the column decreases, Are arranged. These allele groups are associated with α set at ≤0.05. Means were more significant for the ≤335 bp group as determined by the If it is less, it is indicated by an asterisk. Stuttering, shopping, pa For the remaining 24 QTVs, except for Nick (which gave the lowest F ratio), The mean was highest for subjects carrying the ≦ 335 allele.   Statistical analysis. The MANOVA results for all 27 QTVs were gender (p = 0 .012), learning problems (p = 0.023), gambling (p = 0.025), and mania (p = 0. 025) was significant. Stepwise multivariable regression analysis of all 27 QTVs simultaneously The variable elementary school problem (p = 0.012) and gambling (p = 0.03) 8) was significant. r^TwoBased on the values, the MAOA gene is only 3.9% or these The QTV variation has been described. Using χ-squared analysis, subjects with ≤335 alleles There was a significant progressive decrease in% of subjects, TS probands with ADHD (24%, n = 1 From 29), to TS probands without ADHD (20.0%, n = 50), relatives with TS (12.5%) %, N = 16) and non-TS relatives (5.6%, n = 56) (p = 0.003).   Substance abuse group. Control vs ATU subjects. 160 tailored controls The distribution of the four allele groups was as follows: <320-3 4.4%, 320-333-38.1%, 334-335-21.3%, ≦ 335 6.3%. 120 ATU subjects For, the frequencies were as follows: <320-39.2%, 320-333-18.3%, 33 4-20.8%, ≤335-21.7%. These are significantly different, χ^Two= 22.17, p = 0.00006. The frequency of the ≦ 335 bp group can be compared in the two control groups, San Berna 8.9% for the rdino group and 5.2% for twin parents (χ^Two= 0.7 44, p = 0.38).   MANOVA. MANOVA for alcohol and drug scores, The MAOA gene showed a significant association with the VNTR allele, which was A) Drug score (p = 0.001) was more significant than (p = 0.012) (Table 21). The results for combined MANOVA were also significant (p = 0.007) . N which is 257 is the sum of 160 controls + 120 ATUs or 280 Less than. Only 97 ATU subjects completed the ASI. And anti Thus, all of the 120 have been diagnosed with alcohol and / or drug dependent DSM diagnosis DIS was closed for proof.   ANOVA. For two scores that represent the mean for each allele group ANOVA is shown in Table 22. For the TS group, the highest average is ≦ 335b Present in the p allele group. For drug score, Tukey test showed The three other groups were significantly lower than for the 335 bp group.   χ2. Whether the MAO gene was preferentially associated with certain types of substance abuse In order to determine whether or not to do so, study 14 related to the type of drug used. Solid. ATU subjects with control vs. no action (no ATU) vs. ATU subjects with action (ATU Table 23 shows the frequencies of the ≦ 335 bp allele group in 14 types of drugs Since the substance use variables were examined, only those with p of 0.0036 (0.05 / 14) or less were Bonferroni It is considered significant by correction. Only those where p is <0.01 are shown. The exception is al Call dependent only. This is <335 bp in subjects with alcohol dependence. Allele frequencies include those with drug dependence or drug and alcohol dependence. Explain the fact that there was little increase only when compared to those with Is shown. Drug dependence, on the other hand, is the only variable that gave the highest value. Yes (χ^Two= 17.4, p = 0.00003).   regression analysis. Allele group (<335 vs. <335) vs. regression analysis of drug dependence diagnosis The results gave the following result: r = 0.25, r^Two= 0.0625, T = 4.305, and p ≦ 0.0001).   Substance abuse. Enzyme levels (Wiberg et al., 1977; Gottfries et al., 1975; Devor et al., 1994) Using both Vonknorring et al., 1991) and genetic variants (Vanyukov et al., 1993) Previous studies have suggested a role for the MAOA gene in drug abuse. The results here are Are consistent with these conclusions, especially for drug dependence. MANOVA is MAOA Showed significant association between alleles and both alcohol and drug scores However, there are numerous co-morbidities of these two forms of substance abuse. Shown in Table 23 When drug dependence and alcohol dependence are examined separately, as Significantly greater between call dependence and drug dependence.   Male dominance. ADHD, Tourette's syndrome, behavioral disorders, ODD, dyslexia, learning disorders Stuttering, drug addiction and alcoholism all showed male dominance. male Predominance in X-linked is probably due in part to hormonal and environmental factors Genes can also be factors. For the TS group, r using the regression coefficient^Two The determination is that the MAOA gene for different QTVs, but no more than 2. X-linked MAOA gene shows that the variance accounts for 5% or less. It suggested that it did not explain the male predominance of S, ADHD or related diseases. And anti The absence or presence of the ≦ 335 bp allele versus the r.^TwoIs Suggested that up to 6.2% of the variance could be due to the MAOA gene. this is, May play a modest role in drug-dominated male dominance.   Longer minisatella with specific QTV in Tourette syndrome group The allele association was modest, as shown in Table 21, but not for all. There was a significant degree of uniformity in the tendency to cross QTV. This is, by chance, random Although it may have been relevant, we have found that these results It was sought to determine if it could be reproduced with a completely different group of trawls. This Group (drug abuse group) had better MAOA VNTR than observed in the TS group. Showed a stronger association between the longer alleles, especially the ≦ 335 bp allele. The patterns for the two groups are strikingly similar, with ≦ 335 bp alleles The highest score for the offspring and the lowest size allele (<320) Higher scores and intermediate scores for the 334-335 bp allele . This correlation with the size of the repeated allele indicates that the minisatellite itself Consistent with the possibility that it plays a role in the regulation of the MAO gene.                                 Example 3         Dopamine D2 receptor polymorphisms associated with schizophrenia / avoidance behavior   Subject selection and test dosing. We recruited white Bong Tia. The average age is 58 men and 71, 40.9 ± 1.8 and 47.3 ± 1.5 (mean ± SD) years old, respectively There were women's applications. the Millon Clinical Multiaxial Inventory (MCMI-II ) Before taking the second edition of the computerized assay, 1 5 cc of blood was drawn. Due to concerns about race and ethnicity, blood Sources from non-Spanish northern and western European Caucasians, with a few exceptions It should be noted that. Because the most advanced data about controls is Because it is obtained from this group. The study included a total of 129 psychiatrists. Genetically ill patients (with or without substance or alcohol abuse) Child typing and the Millon Clinical Multiaxial Inventory (MCMI-II) Selected for both evaluations. The group consisted of: mood modulation (22. 1%), general anxiety disorder (8.4%), monopolar (24.5%), bipolar (12.9%), schizophrenia (5.2%) , Attention deficit disorder (21.9%), and drug use disorder (18.1%).   The Millon Clinical Multiaxial Inventory was used to analyze Eleven known individual diseases, including the fissure / avoidance cluster, were evaluated. This exam is Includes 175 items, and most people finish it in 20-30 minutes I can do it. Each of its 22 clinical scales comes from theories of personality and psychopathology It was constructed as a work scale for the syndrome of illness. Clinically determined scale is the formula Directly compatible with the diagnostic system and its syndrome category (DSM-IV). Another Scale is built alongside the DSM-IV model, acute clinical injury (Axis I) Distinguish the more persistent personality characteristics of the patient (Axis II). Analyzed standard score change Rather than use the base percentage data of the records to calculate and quantify scale measures did. A basal rate 60 implies a fault. The basal ratio between 75 and 83 is chronic or Indicates moderately severe impairment and, if greater than or equal to 84, uncontrolled Indicates a pathological disorder. In this study, we studied the behavioral Mill in subjects. Identify study groups by using schizophrenia avoidance clusters Selected 84 or higher percentile rank for this specific cluster Was achieved. We assign subjects according to their MCMI-II score. Categorize and group probands into four distinct basal rates according to the following categories: (1) score less than 60; (2) up to 73 equal to 60; (3) 83 equal to 74. And (4) up to 100 equal to 84. The demographics of the subject population are listed in Table 24. Put on.  The MCMI-II test score is based on the Minnesota Multi-Phasic Personality Inventory (MMPI ) Different hospitalizations by comparing 104 patients using the Personality Disorder Scale Justified for the elderly population. Use conservative significance levels to ensure legitimate conclusions I made it. Corresponding MCMI-II measure and schizophrenia, avoidance, dependence, hysteresis , And measures of narcissism were significantly correlated, but passive-aggressive and schizophrenic , And the boundary measure were not correlated. Therefore, this causes Personality dispositions (Shuler et al., 1994; zimmerman et al., 1994: e.g. The use of this test to reliably measure (d) is justified.   For this study, we screened 30 "super" control subjects , Many reward deficient behaviors (alcoholism, multiple drug addiction, smoking behavior, carbohydrates) Glut, BMI> 25, family history of substance abuse disorder, ADHD, morbid gambling, and axis II diagnosis (SAB ) Is excluded and the subject is treated with DRD_TwoA₁And A_TwoAlleles Genotype was determined. More control is on three sources of volunteers From: A) adoptive, foster, step-parents of Tourette's disease patients; B) thyroid cancer or A subject in an endocrinology clinic with non-surin dependent diabetes; and C) a profession Hospital personnel, including technicians, administrative staff, and staff. Script all 142 controls To eliminate ADHD, alcohol, drug and tobacco abuse. Inventors Has 91 of these controls genotyped for DAT19 and 10 alleles. Decision And D51H B₁And B_TwoAlleles genotyped . One important note to consider is the relationship between dopaminergic alleles and SABs. Patient selection to evaluate the run. We believe that coexisting RDS behavior Possible confounding with subjects with (Drug abuse disorders), we found that all RDS in patients showing SAB He also recognized that it was quite difficult to eliminate behavior. Therefore, We must wait for further research in order to address this issue specifically. I have to.   Genotyping. In this study, one or more dopaminergic genes The total number of subjects genotyped for was 271. All subjects are Based on neutral identification numbers and readings without knowledge of the individual being determined Genotyped.   DRD_TwoPolymorphism. D_TwoA₁And D_TwoA_TwoGenotyping described (Blum et al., 1990a; Comings Performed by Southern blot hybridization as described in did. Many samples are also PCR^TMGenotype determined by technology (Noble et al., 1994d) did.   DβH polymorphism. d'Amato and co-workers (d'Amato et al., 1989) have identified A and B Reported the presence of two Taq DβH polymorphisms. 2.7Kb insert at EcoRI site The DβH cDNA clone AII (Lamouroux et al., 1987; Lamouroux et al., 1993) was used. Was. The vector was digested with BamHI and SalI to improve labeling and Occurred. The 3.5 Kb fragment was labeled to test for β polymorphism. TaqI Digestion with restriction endonucleases, electrophoresis on agarose, nylon Southern transfer to Luther, hybridization with 32P-labeled probe 2.8 Kb (B₁) And 1.4 Kb (B_Two) Fragment Prove that.   DAT₁Repetitive polymorphism. Allele of 3'UTR is PCR using oligomer^TMAnd Vandenb PCR reported by erg et al. (1992b)^TMDetermined by conditions. PCR^TMAfter amplification, the product Electrophoresis on an 8% acrylamide gel and visualize using a set of size markers Awakened. statistics. Piazzon's χ^TwoUsing the test and Fisher's exact test, 2 The ratio was analyzed for the × 2 contingency table. Larger contingency tables (eg, 2x3 contingency tables) And Piasson's χ^TwoTest and linear trend for the Mantel-Hensel test ( The test was performed using the Mantel Hensel Test for Linear trend). The difference between the average values Tests were performed using the -dent's t test. Multi Logisti regression c regression) to predict the probability of having a high fission / avoidance score. The contribution of one or several variables was analyzed. Logistic model Hosmer-Lemeshow goodness of fit, recipient manipulation by computer program Proc Logistic C statistic representing the area under the receiver operating characteristic (ROC) curve Item, and r^TwoOr assessed using the presence of causal variance. Any logistics Odds ratios for the predictors in the stick regression model were also calculated (Dun n and Clark, 1995).   result. MCMI-II fission score greater than 84 for the fission / avoidance dataset Limits the potential association between dopaminergic alleles and MCMI-II avoidance scores Χ^TwoAnalysis was performed using the approach to confirm the severity of the proposed phenotype. D RD_TwoA₁Alleles were 50% (11/22) in mitotic subjects and 44% (12/27) in avoidable subjects. Found in test subject; DAT₁480 bp (VNTR 10/10 allele) is 72% (13/18) DβHB found in test subjects and 62% (13/21) of avoidable subjects;₁The allele is 81. Found in 3% (13/16) fissionable subjects and 82.4% (14/17) avoidable subjects . χ^TwoBy DRD_TwoA₁Allele is DRD_TwoA_TwoDivided / evaded compared to allele (MCMI-II score ≥84)^Two= 7.6, df = 1, p < 0.006). DRD_TwoA₁Allele homozygotes are members of the SAB cluster (≥84) The highest percentage of patients with a membership. Heterozygotes are homozygous groups As about half of the SAB patients. Meanwhile, DRD_TwoA_TwoGroups that have only expressions Showed the lowest percentage of SAB (linear trend analysis: p <0.005, A₁/ A₁= 83%, A₁/ A_Two = 41%, and A_Two/ A_Two= 23%).   But DRD_TwoA₁Unlike allele data,^TwoThe analysis was DβH B₁Allele And DAT₁ Can't clarify the association between 10/10 alleles and fission / avoidance behavior Was. DRD_TwoLodgis tests for significant relationships with alleles, age, and gender DRD using bivariate SAB score multivariate association with tick regression_TwoA₁Allele Child And gender were both significant predictors of SAB severity. The inventor And DRD_TwoA₁An allele is found to have an odds ratio of 2.79 (p = 0.018) and Means an odds ratio of 3.6 (p = 0.0031). Hosmer-Lemeshow goodness of fit is p = 0.78 Met. 30 screened supercontrols (alcoholism) , Polydrug dependence, body mass index less than 25, smoking behavior, family history, morbid gambling, ADHD DRD (excluding schizophrenia / avoidance behavior)_TwoA₁Allele prevalence is 1/30 It was 3.3%. DAT in 91 screened controls₁ 10/10 pair The prevalence of the allele was 34/91 or 37.4%, and 51 screenin DβH B₁Allele prevalence is 27/51 or 53% there were.   DRD_TwoA₁Literature control 185/714 for allele (18/37 or 48.6%) That is, 26% (χ^Two= 9.2, df = 1, p = 0.0024; OR = 2.71) and super control (χ^Two= 16.8, df = 1, p = 0.00004; OR = 27.5), and when SAB ≧ 84 , A significant association was found. In addition, significant associations were Roll (χ^Two= 6.3, df = 1, p = 0.012; OR3.0), SAB (18/28 or 64 .3%) in individuals diagnosed with₁ 480 bp (VNTR 10/10 allele) Was also found. Screened controls (χ^Two= 2.89, df = 1, p = 0.09; O R2.52) compared to DβH B evaluated to have SAB (18/20 or 64.3%)₁versus A similar trend was found in progeny carriers. Logistic regression analysis Using statistical techniques, all cases with an MCMI-II score below 84 Compared to all cases with an I-II score above 84 (severity score), DRD_TwoA₁Allele Is statistically significant (χ^Two= 7.5, df = 1, p = 0.0059) accounting for 8.3% of the variance. Contrast And DAT₁(10/10 alleles) account for 1.6% of the variance; DβH B₁Allele is 0.002 It accounts for 5% and the contribution to variance is not significant.   Examining gender as a single variable in a logistic regression model shows that German contribution to overall diversification was 9.9% (％^Two= 9.4, df = 1, p = 0.0022). DRD_Two A₁More than 84 highly mitotic / evasive Ms using alleles and gender as predictors In logistic regression models that predict CMI-II scores, these predictors Odds ratio is DRD_TwoIt was 2.79 for the gene and 3.55 for the male. Hosm The er-Lemeshow goodness of fit p-value = 0.778, and the C statistic (area under the ROC curve) = 0.714. Yes, the combined contribution to variance was 17.9%. In addition, DRD_TwoA₁And A_TwoConflict In a pilot study of 67 subjects genotyped for the gene, Using the procedure, we determined that the other 10 personality elements assessed by the MCMI-II test It was found that none of the qualities were relevant.   In conclusion, we have identified an abnormal personality called the fission / avoidance cluster. To elucidate the contribution of three dopaminergic gene polymorphisms to predisposition Next, we performed an association study using the MCMI-II self-reporting computerized test. Observed The relevance did not appear to be due to population stratification. Because it is Because it was independent of the subject's ethnicity, gender or age. In addition, general The frequency of disruptive / avoiding behaviors based on demographics was 1-4%. To the overall variance DAT₁(10/10 repeat allele) and DβH B₁Significant contribution of both alleles Nothing so far cannot be ruled out due to sample size . In fact, only 44 sample sizes were used (for missing values) These three genetic polymorphisms when combined in a regression analysis demonstrate this complex When there are multiple genes and other factors, such as gender, that are involved in behavioral disorders As can be expected, it accounts for approximately 7.6% of genetic diversity.                                 Example 4          Association of cannabinoid receptor gene with IV drug use   Subject. To minimize race as a confounding factor, all subjects were Restricted to panic whites. The control group consisted of 62 senior students (SB (Troll) and 52 subjects (LL control). In the latter case, 40% Maintenance staff, 43% consisted of secretaries and clerks, and 17% consisted of doctors or doctors . There were a total of 114 controls in both groups.   Evaluation. Based on personal interviews, LL for drug or alcohol abuse / dependence Removed from control. All controls are in Michigan Alcoholism Se verity Test (a 24-item self-applied questionnaire reviewed to include substance abuse; MAST-R). All SB controls whose MAST-R score exceeds 4 Was excluded. In addition, all ATU subjects were tested for the presence of a drug-dependent disorder. Diagnostic Interview Schedulc (DSM-III-R version) (To assess the range of alcohol and drug use variables as described in Example 4) Evaluation) using physician's Addiction Severity Index Fifth Edition .   Genotyping. DNA was extracted from whole blood by standard procedures. By Dawson (1995) The DNA sample was amplified using the following primers as described: 5'-GC TGCTTCTGTTAACCCTGC-3 '(SEQ ID NO: 3) and 5'-TACATCTCCGTGTGATGTTCC-3' (sequence No. 4). This is (AAT)_nAlleles of the triplet repeat were identified. PCR^TMproduct 0.1 μM of each primer was added to the fluorescent agent HEX Amidite (Applied Biosys tems, Foster City, CA) primers. 2 μl 10-fold diluted PCR^TMBirth The product was loaded on a 6% polyacrylamide gel and VNTR polymorphism was described in Example 2. PCR^TMAnalyzed as described for polymorphism analysis.   Statistical analysis of allele and genotype frequencies. Control vs. ATU subjects The frequency of different alleles in the study was determined by George Carmody (Carleton Univ, Ottawa, Cana). recursive Monte Carlo test for significant differences using the R × C program by da) (Roff and Bentzen, 1989). The advantage of this computational approach is , With estimated standard error^TwoThe simulation is performed with a small number of observations (especially 0) Can be completed without denting. The frequency of different genotypes^TwoAnalysis Used and compared.   Factor analysis. Preliminary limited to only two factors to deal with the statistical problem of multivariable analysis Factor analysis was performed. Factor 1 combines variables for drug dependence While factor 2 is used to combine variables related to alcoholism. Contributed.   Alleles and genotypes. We consist of 1, and 3-10 repeats Nine different alleles were observed, but the controls in this study were also None of the subjects had the biallele. Control and ATU test The distribution of the nine alleles in the body indicates that the most common allele was # 4. And This is 36.4% of controls, 31.7% of ATU subjects, and IV drugs Was present in 20.2% of ATU subjects using. The working hypothesis of the present inventors (Coming s, 1996b; Comings, 1996a) are microsatellite (mainly due to the formation of Z-DNA) Hamada et al., 1982; Schroth et al., 1992) play a direct role in gene regulation. And the magnitude of the effect depends on the length of the iteration. Was. The main group of alleles is four repeats and one or three alleles are present. Since there were very few, this was the case for shorter alleles (<5) and Natural splitting of the nine alleles into two groups consisting of Made it possible. This produces three genotypes, <5 / <5, heterozygotes, and ≦ 5 / ≦ 5. I did Remove any other alleles, genotypes or pairs to remove statistical complexity No progeny combinations were also tested.   ANOVA. To further remove the statistical complexity associated with large numbers of variables, The first test of the data included factor 1 and 2 versus the above three genotypes by ANOVA. Testing was included. Using this, a later test was performed mainly for the recessive model (<5 / <5 vs. B zygote + ≦ 5 / ≦ or ≦ 5 / ≦ 5 vs heterozygote + <5 / <5); or dominant model (<5 / <5 + heterozygous pair ≤5 / ≤5, or ≤5 / ≤5 + heterozygous pair <5 / <5) Or heterozygous (heterozygote pair ≦ 5 / ≦ + ≦ 5 / ≦ 5) Was. The results suggested a recessive model of ≦ 5 / ≦ 5 versus heterozygote + <5 / <5. again, No other models were tested to remove statistical complexity. Factor 1 or factor If any of the offspring 2 produced significant results, the Some of the cores were studied by ANOVA using a recessive model.   χ^Twoanalysis. The individual variables highlighted by the significant factors are 2 × 3χ^TwoUse test And further evaluated. × 2 dimension is two genotype groups-≤5 / ≤5 repeated alleles Homozygous for the offspring versus the remaining "other" genotypes. The dimension of × 3 is (1) Control, (2) ATU subject scored 0 for a given variable (ATU negative) (3) Consisted of ATU subjects that scored ≧ 1 for a given variable (ATU positive). ATU negative Adding groups tested increased frequency of ≧ 5 / ≧ 5 genotypes in ATU subjects tested Eliminates the possibility of a factual association with a coexisting obstacle or variable other than Was needed to We predicted three patterns:   A. Significant-linear. If ≧ 5 / ≧ 5 genotypes are associated with a given variable, we will Negative for that variable in ≧ 5 / ≧ 5 groups progressing from control to ATU-negative case Significant linear-like increase in the proportion of sexually transmitted cases, progressing from control to ATU-positive cases Significant linear-like increase in the proportion of cases positive for that variable in the ≥5 / ≥5 group Predicted. The significance of this progressive increase is determined by the linear χ^TwoCertification test (SPSS Statistical P Mantel-Haenzelχ of ackage (SPSS, Inc., Chicago, IL)^Two). Since ≧ 5 / ≧ 5 genotypes could be associated with more than one substance or variable, we In addition, the ratio of ≧ 5 / ≧ 5 carriers is less in the ATU-positive group than in the ATU-negative group. Also needed to be 20% higher.   B. Significant-non-linear. ≧ 5 / ≧ 5 genotype is the ratio of ≧ 5 / ≧ 5 gene carriers Is higher in the ATU-negative group than in the ATU-positive group, even when the p-value is significant , Was considered unrelated to the given substance.   C. Not significant-non-linear. ≧ 5 / ≧ 5 genotype also has a p-value> 0.05 It was considered unrelated to the given substance.   result.   Subject characterization. ATU subjects with an average age of 39.7 years (S.D.7.0 range 23-52 years) Was compared to controls with an average age of 38.4 years (S.D.12.6 21-71 years). There was no significant difference (F ratio = 0.76, p = 0.38). All ATU subjects are male Was. On the other hand, 45 (39.5%) of the controls were male and 69 (60.5%) were female. Was.   Allele frequency. ATU subjects using the drug intravenously were selected. Because Clinical experience has shown that such subjects have the most serious problem of drug dependence. Because they represent people. The frequency of all alleles was determined by Monte Carlo test When compared to the control vs. ATU group using 2,000 replicates, There was no significant difference (χ^Two= 7.09, p = 0.54). Control compared to IV drug user When compared, the difference was on the border (χ^Two= 14.49, p = 0.065).   For the control, 41 or 36.0% were ≧ 5 / ≧ 5 homozygotes, On the other hand, 43 or 46.7% of ATU subjects were ≧ 5 / ≧ 5 homozygotes (p = NS). 32 people Of the IV drug users, 20 or 62.5% were ≧ 5 / ≧ 5 homozygotes (χ^Two= 7.2 3, p = 0.007).   There were females in the control group, but males in the control group (37.8%, n = 45) There was no significant difference in the prevalence of ≧ 5 / ≧ 5 genotypes in females (34.8%, n = 69) (χ^Two= 0.10 6, p = 0.74).   Factor analysis. Factor analysis was set up to create two factors. Factor 1 is related to substance abuse. To be made up of variables. These include the IV use of the drug, the number of Drug age, drug score, and diagnosis of some forms of drug dependence DSM Consists of variables. Factor 2 is the number of DUIs, wasting money on alcohol, alcohol Severity score, number of alcohol detoxifications, alcohol score, and alcohol Contributed to consist of variables related to alcohol use such as DSM diagnosis of dependence.   Table 25 shows the results of the ANOVA analysis of factors 1 and 2. The average Factor 1 score is <5 / <5 Alleles (-0.085) are heterozygous (-0.151) or homozygous Subjects homozygous for ≧ 5 / ≧ 5 allele (0.198) than for subjects The highest for the body (F ratio = 2.85, p = 0.060). This means that ≧ 5 Homozygosity for the gene> 5 heterozygotes for the 5 repeat allele "other" + e A recessive model of mozygosity was suggested. When this model was tested by ANOVA, ≧ 5 The average of factor 1 for those with genotypes of ≧ 5 is factor 1 for those with “other” genotypes Was significantly greater than the average of (p = 0.019). In contrast, for the mean of factor 2, There was no significant difference between the three genotypes and the recessive model. won.   These first results are related to drug dependence but not alcohol dependence. Not consistent with alleles of the CNR1 gene. To test this further, the inventor Used a recessive model to determine the average alcohol score, drug score and IV Tested against number of objects (Table 26). Average drug score for those with ≧ 5 / ≧ 5 genotypes Was significantly higher than the average score for those with other genotypes (p = 0.038). vein The average number of drugs used within (#IV) is also better for the other genotypes (p = 0.005). And significantly greater for ≧ 5 / ≧ 5 homozygotes. This is 0.5 / 3 or 0.01 Using Bonferroni calibration α of 6 was still significant. In contrast, "other" genotypes Substantially no difference in average alcohol scores for ≧ 5 homozygotes compared Was. To exclude the possibility that age is a hidden covariate explaining this result, Age was used as a covariate. The p-value for age is 0.404, while the The required effect was 0.004. This suggests that age variation does not explain this result. Is shown.   The association with the average drug score suggests that the CNRI gene is Led to the question of whether it could show a greater association. Four types of drug dependence 2 × 3χ outlined in the method^TwoTested using analysis (Table 27). Three types Drug dependence showed a significant increase in the frequency of ≧ 5 / ≧ 5 genotypes across the three groups : Cocaine, amphetamine, and cannabis dependence. What is opioid dependence There was no meaningful connection. None of these are Bonferroni schools at 0.05 / 4 or 0.0125. Not significant using positive α.   Alcohol dependence alone was also included for comparison. Alcohol dependence ATU subjects without alcohol dependence (29.6%) 0.7%) had a ≧ 5 / ≧ 5 genotype.   Routes of cocaine, amphetamine and heroin administration. Table 28 shows these drugs. The results for the administration route are shown. For cocaine, the prevalence of ≧ 5 / ≧ 5 genotypes From 36.2% for ATU subjects and controls without cocaine, Up to 32.3% of those who inhale cocaine and those who smoke cocaine Up to 55.6%, up to 68.4% for those injected with cocaine (p = 0.006) . Similar results were obtained for the amphetamine route of administration and no cocaine 35.7% of those have ≧ 5 / ≧ 5 genotypes, whereas amphetamine is injected intravenously 65.2% (p = 0.007). For those who use IV heroin An equally high frequency of ≧ 5 / ≧ 5 genotypes was noted.   regression analysis. Estimate the percentage of variance of the three quantitative scores due to the CNR1 gene To obtain, we performed a regression analysis. Here, the genotype is ≧ 5 / ≧ 5 2 for those with the genotype and 1 for those with other genotypes (Table 29). The CNR1 gene has a total alcohol score of substantially 0 They accounted for 2.1% of the drug score and 3.8% of the IV drug score (p = 0.005).   The results show that many different types of drug dependence (cocaine, amphetamine, cannabis) , And significant association of the CNR1 gene with IV drug use (particularly severe forms of drug dependence) Is shown. The results of this application demonstrate the first described link between a particular gene and IV drug use. Communicating I will provide a. In contrast, there was no significant association with the variables for alcohol abuse / dependency. Absent.   Another explanation for this possible result is that both groups were restricted to non-Hispanic whites. Nevertheless, the hidden ethnic stratification of ATU subjects versus controls has It is to explain. This has always been a concern in related experiments, Association of ≧ 5 / ≧ 5 genotypes with substance-dependent variables (but similar demonstrations with ATU substance abuse subjects) Despite having graphics, there is no association with alcohol dependence variables), Larger mix of dopamine reward pathways with most drugs compared to alcohol Perturbation and close interaction between dopaminergic and cannabinergic metabolism Have a consistency that makes ethnic stratification less likely to explain the consequences Age was also excluded as a complicating variable.                                 Example 5    Body mass, psychiatric symptoms and dopamine D2 receptor gene (DRD2)                 Genetic variants of the related human obesity (OB) gene Methods and materials   Health Promotion Center Group (CHP) Subjects from the CHP study were 211 non-Hispanic It consisted of white people. To analyze the power of other studies on the relationship between genetic polymorphisms and behavioral variables Based on this, we looked for sample sizes of 200 to 225 patients. age Ranged from 29 to 75, the average age was 54, and the standard deviation (S.D.) was 10.2. Was. 98 people in this group were male and 113 were female. Age, gender, weight, body Length, and waist-hip ratio were determined for each subject. Total body fat in the water Was determined by weighing. Each subject, from the age of 16 to the current age, At different age intervals, we were asked to provide data on maximum body weight. Blood glue Fasted blood sump to determine course, cholesterol, and insulin I got Coded blood samples without knowledge of CHP data Was analyzed.   NEO5 Factor Personality Inventory (Costa and McCrae, 1992) and Symptom Check for each subject Completed Listing-90 (SCL-90). Subject also answered the following set of questions: Hunger So do you eat? Do you eat? Do you eat snacks between meals? boring Do you eat for that reason? Do you eat from stress? Do you have breakfast ? Do you eat too much at dinner? Do you prefer sweets? Do you like vegetables? Oily Do you prefer a good meal or fried food? . The only possible response is 1, never. 2, sometimes; 3, often; 4, very often; and 5, always .   Genetic studiesThe present inventors, as previously described (Green et al., 1995), D7S1873, D7S1875, D7S514 and D7S680 present in the YAC contig containing the gene PCR nucleotide repeats^TMAmplified. Of these, D7S1875 is closest to the OB gene. Was. We set this as OB₁₈₇₅Call. DRD2 gene Taq A1 allele Inspection was performed using the primers described (Noble et al., 1994b).   OB₁₈₇₅Statistical analysis of genotypes A priori hypothesis is that the D7S1875 dinucleotide repeat Either the shorter or longer allele of the BMI is associated with BMI or another variable. When linked, individuals that are homozygous for the short (or long) allele are Heterozygous individuals have the highest score, heterozygous individuals have intermediate scores, and An individual homozygous for the (short) allele has the lowest score, That is. Therefore, the ANOVA integration of SPSS (SPSS, Inc., Chicago, III) The subcommand "many" tests the mathematical program for progressive linear relationships. The average of the behavioral scores can be calculated for different allele groups using the Were compared. If three or more groups are present, By analysis, α = 0.05 was tested for individual significant differences between any groups. Co-dividing Scatter analysis (ANACOVA) to share BMI, waist-hip ratio, age and gender. OB for SCL-90 anxiety score, using as variable₁₈₇₅The effect of genotype was tested. In addition, three OBs for variables with dichotomous breakpoints₁₈₇₅About genotype Te^TwoAn analysis was performed. A priori assumption is that three OBs₁₈₇₅Progressive linear increase between genotypes Since there was an addition or a decrease, they were linear χ^TwoTest (SP Mantel-Haenszelχ in SS^TwoTest). Finally, use regression analysis Then, the correlation (r) between OB and DRD2 genotype or allele was determined. r^TwoIs Related remains The percentage of variance described by the gene or gene combination was provided. result   The BMI averaged 27.9, S.D.7.2, and ranged from 17.7 to 57.6. For the first study Alleles of all four polymorphisms are assigned to the longer group and Tested by splitting into shorter groups. Subject to shorter allele Homozygous for longer alleles And those that are heterozygous for the short and long alleles Genotyped. Testing for BMI in these three genotype groups indicates that the D7S1875 polymorphism It has been shown to give the highest F ratio. Therefore, all other variables Subsequent studies were performed using this polymorphism.   OB₁₈₇₅Allele distribution. OB for CHP subjects₁₈₇₅Alleles with different polymorphisms The offspring ranged in size from 199 bp to 225 bp in length. Dizziness in psychiatric disorders Our a priori approach to testing nucleotide repeats (Comings et al., 1996c) First approximate alleles if there is a natural tendency for the bimodal distribution Was to divide into groups. This is OB₁₈₇₅In the case of polymorphism, Was made at 208 bp. The obtained genotypes were <208 bp / <208 bp, <208 bp / ≧ 208 bp , And ≧ 208 bp / ≧ 208 bp.   Obesity variables. For the entire group of men and women, there is a significant association only with body weight , Decreased progressively across the three genotype groups (<208 / <208 n = 47, 183.83 kg, S .D. 45.39; heterozygote n = 95, 177.56 kg, S.D. 44.00; ≧ 208 / ≧ 208 n = 39, 16 1.29 kg, S.D. 45.17, F ratio = 5.22, p = 0.023). About BMI, <208 / <208 homo From 28.92 for zygotes, to 27.96 for heterozygotes, and ≧ 208 / Progressive but insignificant BMI reduction up to 26.62 for ≧ 208 homozygotes There was. Plasma insulin, fasting blood glucose, cholesterol and fat Mean genotype differences in rates were not significant. Place where individual gender was tested For men, the trends were the same for men. BMI reached significance (p = 0.053), body Weights were significantly different (p = 0.038). The trend was again the same, but all variables were female Only for one was not significant.   BMI by age. Table 30 shows the different subjects for both men and women Figure 5 shows ANOVA comparison of average BMI at age. The genotype difference is Is significant when they are 26-30 years old, and when they are 16-20 years old It was almost significant. Again, when testing only women, the group between the ages of 26 and 30 was significant. (P = 0.028). When only men were tested, neither age group was significant Did not. BMI when subjects were between the ages of 26 and 30 were divided into three groups: <25, 25-34, ≧ 34 Divided into OBs from 24% to 33% and 56% across three BMI groups₁₈₇₅<208 / <2 08 The frequency of genotypes increased progressively (linear^Two= 4.46, d.f. = 1, p = 0.034).   SCL-90. Table 31 shows the results of SCL-90. Scores for <208 / <208 homozygotes are not Anxiety, depression, psychosis, hostility, paranoid thinking process, intimidation, symptom total ), General symptom index, and overall total ) Was significantly higher. For seven of these scores, p is less than 0.025 Was.   Analysis of covariates. Psychiatric variables are simply secondary to weight problems or types of obesity OB to test a possibility₁₈₇₅Genotype as the main effect, and BMI, c SCL-90 anxiety score using est-hip ratio, age and gender as covariates Were tested (Table 32). This is OB out of five variables₁₈₇₅Only genotype, anxiety score A significant association with a. SCL-90 score, depression, total Positive symptoms and total symptoms are correct.   DRD2 and BMI age groups. D_TwoA₁ANOVA for presence or absence of allele Run and DRD_TwoWhether genes also play a role in age-specific BMI Decided. The average BMI is for the A1 allele of BMI when subjects are between the ages of 31 and 40. Significantly higher (D_TwoA1 + n = 54, 28.78, S.D.8.56; D_TwoA1− n = 70, 25.67, S.D.5.21, F ratio = 6.04, p = 0.015). As with the OB gene, The F ratio tended to be lower for the older group, but the sample size also It was smaller.   OB combined₁₈₇₅<208 / <208 homozygosity and D_TwoA1 allele. OB and D To determine if the effect of the RD2 gene is additive, BMI and OB₁₈₇₅ Homozygous for the <208 / <208 allele and / or D_TwoA1 conflict Heredity They were tested by dividing them into those that had offspring (Table 33). These results are non- It was always significant. OB₁₈₇₅Homozygous for the <208 / <208 allele, And / or DRD2 D_TwoSpecimens carrying the A1 allele are 16-20 years old, 21-25 years old, 26-30 years and 31-40 years had significantly higher average BMI. The effect of these two genes When the results were combined and the entire set of biopsy variability tested, the difference was Significant in hip ratio (p = 0.033), body weight (0.013), and insulin level (0.042) there were.   regression analysis. Univariate regression analysis is based on the age characteristics of the OB gene or OB + DRD2 gene. Unusual BMI fluctuation (r^Two) (Table 34). Both men and women For the OB gene only, r and r^TwoIs B at the age of 16-20 and 26-30 Only significant for MI. Here, the OB gene is the variation of these two BMIs Accounted for about 3%. However, when combining the effects of the OB and DRD2 genes, These were the groups of 15-20 years, 21-25 years, 26-30 years, 31-40 years, with 8.5-9.9 of BMI variability. Accounted for%. When only women are tested for the OB gene alone, the correlation is between 31 and It was significant only for the 50-year-old group (p = 0.029). Combination of OB and DRD2 genes When tested for effects, the correlations are 15-20, 21-25, 26-30, 31-40 And for subjects aged 41-50 years. The most significant correlation is 26-30 Age (p = 0.0004) and 31-40 years (p = 0.0005). Where two Genes accounted for 22.8% of BMI variability.   N.E.O. Five N.E.O factors of consent, pruritus, extroversion, nervousness, and openness increase Only significant in the nervous system. Three OBs₁₈₇₅The score across genotypes is 21.16 , 17.82, and 14.86, with an F-ratio of 7.29 and p = 0.008. Diminished habit Syndrome was borderline significant (32.97, 34.67, and 35.65, F-ratio = 3.71, p = 0.056 ).   Reason for eating. Two of the questions about the reasons for eating Beef, and eat breakfast)₁₈₇₅Significant in relation to genotype. For "eat to relieve stress," scores ranged across three genotypes : 2.55, 2.32, 1.85, F-ratio = 4.54, p = 0.034. As for "eat breakfast", 3 .50, 4.15, 4.14, F-ratio = 4.89, p = 0.028.   OB if BMI based on the subject's current weight is used₁₈₇₅About genotype effects There was very little evidence. For intermediate homozygosity and lower Are homozygous for ≧ 208 / ≧ 2008 alleles Thus, while there is a trend towards <208 / <208 homozygosity to have the highest BMI, The results were not significant. Body-to-hip ratio, fat percentage, plasma insulin, and blood sugar Differences were not significant, while differences in body weight were significant (p = 0. 02).   OB for the subject's BMI if the subject is 16-30 years old₁₈₇₅, 208 / <208 homo Subjects tend to be significantly or almost significantly associated with conjugation, but subjects are 41-70 years old If there is little or no relevance for the subject's BMI No. This trend was also true for women alone, but, conversely, for men alone. Tended to be insignificant (Table 30). These results indicate that the OB gene Suggests a correlation of variability between BMI and BMI, but not in older women, There was no correlation with BMI in men of any age. Male and female BMI 2 for <208 alleles when divided into <25, 25-34, and <35 years 4% to 56%, significant and increasing in the percentage of homozygosity of the subject .   The association with psychiatric variability based on SCL-90 was more dramatic. Obesity and most frequent Two actions correlated with anxiety and anxiety are OB₁₈₇₅E for the <208 allele It was significantly correlated with mozygosity (p = 0.003-0.0005). 208 alleles for anxiety The mean score (0.85) of the 36 subjects homozygous for the offspring was 0.277) or more than twice the homozygous (0.203) score. OB₁₈₇₅<208 One reasonable explanation for the association between alleles and anxiety and depression is obesity and anxiety. These alleles that cause depression and may be secondary to obesity. this In order to investigate, we determined that BMI, torso / hip ratio, age, And gender, and OB as the main effect₁₈₇₅Perform covariance analysis using alleles Was. For anxiety, this means that only changes that significantly correlate with the SCL-90 anxiety score are OB₁₈₇₅ ≥208 allele, indicating that the OB gene is a psychiatric disorder Have a primary effect on the condition and directly in depression and anxiety associated with obesity Suggested that it could play a role in causing   Using ANIVA to test the role of the DRD2 gene in CHP subjects, D_Two Variation in subjects with A1 allele vs. subjects without A1 allele BMI at different ages was compared. If you have the OB1875 allele, That is, there was only a significant correlation with BMI for the 30-30 year old group (p = 0.015) .   To examine the additive effects of two or more alleles, we consider that OB1875 < Homozygous for the 208 bp allele and / or D_TwoKeep A1 allele ANOVA was performed on subjects with different age-specific BMI groups. male OB1875 <208 / <208 or D_TwoA1 allele, and 16-50 For all age groups, there was a significant correlation between the presence of any of the higher BMIs. (Table 34). The p-value for all four 16-40 year old groups was <0.005. women only When tested, the results are even more significant, despite the lower number of subjects. Was. Here, the p-value for the 16-40 year old group was in the range of 0.0017-0.0004. Torso to waist ratio Genotype or allele in terms of body weight, body weight, and plasma insulin levels There was a significant correlation for subjects carrying either or both.   In a previous study (Comings et al., 1996f; Comings et al., 1996b; Comings et al., 1997b) As such, the determination of the regression coefficient (r) between the genotype in question and a predetermined score is determined by r^Two Or it allowed the determination of the rate of variation of the score due to the gene being studied. age These results for specific BMI values are shown in Table 34. Combination of men and women The OB gene alone has a significant effect on BMI variability at 16-30 and 26-30 years They accounted for 3.2 and 3.0 percent, respectively. For women alone, these values are 6.2 and 4 Increased to .1%. When the effects of OB gene and DRD2 gene are combined, For subjects aged 16 to 40 years, these genes have BM I accounted for 8.5-9.9 of the variation. When testing only women, these two genes Accounted for 19.1 to 22.8% of the change in BMI score for subjects aged 16 to 40 (p = 0 .0017-0.0004).                                 Example 6                 Additive effects associated with the three dopamine genes   In this study, these three major factors affecting dopaminergic neurons were studied. The additive effect of the gene of interest can be determined by the inheritance of specific markers for all three genes. Samples tend to have higher (bad) behavioral scores than subjects who inherited less than 3 It was studied by determining whether it was or not. Reduction, an interaction of additive effects Subjects that did not inherit these markers at all have a subtractive effect, By determining whether they tend to have lower (better) behavioral scores Was tested. Subjects with one or two markers were intermediate between both effects It was tested by determining if it had a tendency to have a score. This exam is , The essence of polygenotypic inheritance-to produce clinically significant effects in phenotypic systems The need for additive effects of some genes. Method   Subject. Subjects for TS treatment were patients, relatives of patients, TS, chronic Diagnosis of dyskinesia or chronic vocal tics is based on the DSM-III-R criteria (American Psychiatric Association, 1987). The TS proband (n = 225) Defined as individuals seeking medical nursing at the clinic. 82% of probands had TS However, the remaining 18% are chronic motor tic disorders or chronic vocal tic disorders I had Of the relatives of non-starting TS (n = 60), 54% have TS and 31% have chronic He had a dyskinesia and 15% had a chronic vocal tics disorder. Non-TS relatives (N = 13 None of 2) had chronic motor tics or chronic vocal tics. All departures The proband was personally questioned and tested. More than 80% of relatives also personally question I examined. Give each proband and their relatives the racial background and ethnicity of their grandparents I asked about the background. For DRD2 studies only, and northern and southern Europe Includes non-Latin American probands, relatives, and controls with background Was. All subjects were older than 6 years.   Ethnic stratification. In this study, we avoided stratification. North or South Yaw for all subjects Restricted to non-Latin American whites of Loppa ancestry. The ethnic background of each subject is 4 Decided in all grandparents. Most subjects have 4-6 different ancestral groups And the different ancestral groups ranged from 1-12. Screen 714 controls To eliminate alcohol and drug abusers, D_TwoAbout the A1 allele A total of 13 different studies were tested. D in these studies_TwoA1 allele prevalence The rates average 25.9% and range from 12.5 to 34.8%, with 432 TS All were lower than 40.7%. (Super Cont previously described in this application See also rol Study). Average behavior score D_TwoA1 carrier vs non-carrier When tested, some means show that even when controls are excluded from the analysis, It was significant. The same is the combined test of all three dopamine genes Was true about Different subjects score higher in different behavioral scores It was the tendency. Despite this, unaffected controls, unaffected diseases When examining three groups of cases and affected cases, many had significant results. all Opportunities for all these outcomes are, in fact, due to the presence or absence of the tested change. Rather than stratification, it was the result of hidden ethnic stratification. Positive results are All three tested using the same polygenotypic set of trolls and subjects Obtained with two dopamine genes. Hidden ethnic stratification is the inheritance of all three The potential for involvement with the child has diminished. These positive results are simply multiple lines Examining the change in dynamics, the fact that a few should be unexpectedly significant Not a result. We have studied the behavior of some other genes tested. For all of the changes, overall insignificant results were obtained.   Control. Controls (n = 67) were obtained from three sources: a) TS patients B) thyroid cancer or non-insulin-dependent diabetes mellitus Subjects from endocrinological clinics, and c) specialists, technicians, Hospital staff, including staff and mechanics. Both conditions are easily treatable with rapid therapy. Present in a wide range of ages, Source was the same on a TS patient basis, so endocrine patients were selected as controls. I chose. Screen all controls, ADHD, alcohol abusers, drugs Substance abusers and tobacco abusers were excluded.   Structured questionnaire. Since 1987, all patients and first generation relatives available Page 31 modeled after the Siagnostic Interview Schedule (DIS) (Robins et al., 1991) Needed to fill out the action questionnaire in detail. A complete questionnaire is available elsewhere Available (Comings, 1990a). In addition to the DIS questionnaire, There were many questions to ask. All of the DSM-III and DSM III-R variations are diagnostic for ADHD, And the type, location, persistence, and severity of motor and vocal tics Required for questions (American Psychiatric Association, 1980, American Psy chiatric Association, 1987). The responses to these questions are then Entered in the database. Use of this instrument and the symptom cluster The various aspects of the use of sudo are shown elsewhere (Comings, 1995c; Comings, 1994c; Co mings, 1994a; Comings, 1995a).   Blood sample. Blood sample goes to all TS probands or clinics Since not obtained from relatives, the choice is essentially random, within the limits of the following considerations: there were. First, blood sample donation is generally voluntary and many subjects (especially young Person) and did not donate blood. Second, breed and ethnic stratification Non-North and South European white Latin Americans due to problems Blood tended to be collected. Because the most extensive data in controls Data was obtained from this group. Third, both patients are available If one of the patients prefers blood from these families over those who are not available Selected.   Genotyping. Unique identification of all subjects without knowledge of the typed individual Genotypes were determined based on numbers and judgment. D_TwoA1 genotyping previously described The hybridization was performed by Southern blot to obtain (Coing Et al., 1991). Some also use PCR as described previously.^TMGenetic by technology Typed (Dawson, 1986). DβH genotyping was performed as described in Example 3. Was. DAT1 repeat polymorphism was genotyped as described in Example 3.   Criteria for comorbid condition. A structured questionnaire is a set of related symptoms Made the teacher's face possible. Each of these criteria was determined prior to the study. These are Including: alcohol abuse (Comings, 1994b), drug abuse (Comings 1994c), strong Compulsive behavior (Comings, 1994a), major depressive episode (Comings, 1995c), mania (Com ings, 1995b), somatization disorder (Comings, 1995b), panic attack (Comings, 1995b) , Phobia (Comings, 1995b), behavior disorder (Comings, 1995a), rebellious behavior disorder ( ODD) (Comings, 1995a), Sexual disorder (Comings, 1994c), Learning disability (Comings) , 1995b), and tic severity (Comings, 1995a). ADHD score is in the questionnaire The sum of all 22 ADHD variations used is shown. Where none or never = 0, possibly = 1, and often = 2. Previous studies (Knell and And Comings, 1993), a variation with a score of 21 or higher is considered to have ADHD it was thought. Since we are particularly interested in ADHD, we also have DSM- Exactly based on the III-R diagnosis, it was tested using a second set of criteria. Here, at least 8 out of 14 of the above 22 variations were required (Amer ican Pcychiatric Association, 1987).   To be precise, the availability and granularity of a questionnaire based on an approach to symptom assessment Structuring measures (eg, Kiddie Schedule for Affective Disorders and Schizoph renia, both given to the same subject). Have been shown by others by comparing the use of such tools (Karp, 199 4; Grossman et al., 1994).   The following were not issued at the time of this description or required classification A measure for some symptoms or scores that can be. Common in schools To assess behavior (Grade School symptom), we Asked the following questions: "For grades 1-6, your school grades are as follows: Were all below average, average, or above average: a) arithmetic, b) Reading, c) writing. " Possible answer Was: below average (2), average (1), above average (0). The result is the most Evaluated over 3 subjects with bad 6 and best 0. About two minute fluctuation Thus, a score of 4 or higher was considered positive for class issues. Individual Have not been placed in an education-disabled, learning-disabled, learning-disabled or rescue class environment. Therefore, it was considered that he had a learning disability problem (learning disability symptoms). In the subject, DI Ask about all of the 16 phobias (symptoms) of S, and more than 3 If they had difficulty, they were considered to have phobia problems. Phobia score, Expressed as the total number of DIS phobias for a given subject. Depression attacks (depression attack symptoms) "When most people are not afraid, all of the surprise is fear, heart, Spelling or launching when you feel it is very difficult Have you been attacked by cropping (not due to a physiological disease)? " If you answered "yes," it was deemed to be somewhat present. Depression score is predetermined The subjects were indicated by the total number of DIS panic attacks. Reading problem (Ready To assess the reading problem symptoms), "if any, What is the best number of years you feel you are behind your classmates? For example, 6 If you are a fourth grader and have only a 4th grade reading ability, There is a delay. Was individually asked. Those who answered that it was more than two years Was considered to have a problem. Stirring (stuttering symptoms) refers to stuttering problems. Have you ever had anything? " General anxiety (one Individuals who scored positive for general anxiety symptoms) had the following DIS quality Question Answered "Yes" to both: "Excessive anxiety about various things in life." Or have you had a period of concern? "And" Yes " If these feelings were more than they were absent, these feelings would be more than 6 months Did you continue? ". The problem of incarnation (embodiment symptom) If you answered “yes” to three or more of the DIS questions, it was considered A shows the total number of DIS somatization symptoms for a given subject. Sleep problems (sleep Symptoms) are present if one of the following questions occurs daily or almost daily: Thought to be: sleepy at night, sleepy while walking, scary at night, waking up early Can't sleep again, sleep away, or have nightmares. Sleep score The sleep score, which occurs daily or almost daily, is indicated by the total number of symptoms. Sexual disorder Positive if an individual with (sexual symptoms) answers "yes" to any of the following: (Comings, 1994a): 1. 1. Frequent flashers, More often than the average 2. be sexually active; 3. prefer same sex or both sexes; Very entertaining to sexual things 4. tasty Write more obscene pictures in childhood than other children of the same age 6. 6. I have always been born with wrong sex. Halloween 8-11 spectators, dressed in the opposite gender, outside of a virtual or virtual party Being sexually aroused by a child, or by cruel or abusive fantasy For more than 6 months. The sexual behavior score is defined as Shown by the total number of actions. Schizophrenic behavior (schizophrenia behavior symptoms), DIS question of schizophrenia symptoms If more than one answered yes, it was scored as positive. Schizophrenia score Indicates the total number of DIS schizophrenia symptoms in a given subject. The subject is examined for eight different Questions about the onset and age of a new motor tic and nine different vocal tics Was examined for tics (tic symptoms). The number of such ticks And added until a scoring occurs. Therefore, the presence of a plurality of different tics is Scored higher than his tic. The above is dichotomous for chi-square analysis Result, and carrier vs non-carrier D_TwoTo compare means in A1 alleles Scores provided.   Grouping of cases. With the above information, it is possible to divide the subjects into two different groups. Came. The first group is the presence or absence of chronic motor tics and / or vocal tics These groups, based on the number of TS probands with TS problems, TS or chronic tics, Relatives, relatives of TS probands without chronic tics, and controls without tics It was. The second group includes: a) drug abusers, alcohol abusers, or tobacco Controls that are not abusers and have no behavioral status of questioning (unaffected B) TS proband or relatives who are not active TS proband or its relatives who have the behavioral symptoms of Case). Thus, for example, the control and the subject Now that the answer is over, the comparison of compulsive behaviors Non-compulsive controls, non-compulsive TS probands and their relatives, compulsive Performed between compelling TS probands and their relatives. In a multi-genotype set Only 3% of TS probands are mild, 74% are moderate, and 23% I was serious.     statistics. When testing an individual's behavior (eg, behavior x), a TS with behavior x Significance in morbidity of markers in controls with no odds vs. behavior x There are two possible reasons for the increase: a) The marked gene is Or b) the marked gene may be associated with behavior y However, since y itself is related to the behavior x, it frequently increases. Distinguish between a) and b) For this reason, we have three groups (control "none" (no x and y Unaffected cases (no x but often y), And the affected cases (x and often y)) A significant, progressive, linear increase in the incidence was required. SPSS (SPSS, Inc. Chi cago, IL) Statistical package was used. Unaffected controls vs. affected For a series of unaffected versus affected cases compared to the dichotomous variation In this case, SPSS Mantel-Haenzelχ squared statistics for continuous linear trend were used. D_TwoA1 pair Subject with progeny (D_TwoA1A1 or D_TwoA1A2) Test without A1 allele Body (D_TwoFor comparison of the average of predetermined behavioral scores in A2A2), Student's t-test Was used.   Due to the homogeneity of each gene studied, we have identified three different genes. And the same group of subjects were genotyped. This group was called a multi-genotype set. Suffered Samples should be included in this set before genotyping for DβH or DAT1 alleles. Placed. The selection criteria for a polygenotype set is that the subject is non-Latin American Must be white, have to fill out a structured questionnaire, get blood Enough DNA to genotype all three genes that must cooperate And provide control, TS proband, or proband's parent Had to be one of a kind. Since we tested the same subject, Allowed the average behavioral scores to be compared for different genes.   There are 319 subjects in the polymorphism set. In addition, a significant number of subjects One, but not all, of the genes were genotyped. For each gene, Were referred to as the total set and varied in size for different genes. all The total set of symptoms is a polygenotype set + a further non-polygenotype set Including symptoms. To avoid losing data or force, the total set of p-values Only in the last column of the appropriate table. Alleles tested by t-test analysis Or a subject with a marker versus an allele or subject without a marker The means of different behavioral changes were compared. Furthermore, if appropriate, the total set of p-values They are listed in the last column of each table.   For a quantitative test of the mean of different behavioral scores, we have two I drew the opposite strategy. The first is that as more subjects are tested, type II Test as many subjects as possible, assuming that the likelihood of Is Rukoto. Relatives and TS probands for this strategy control Tested. The second strategy has the least degree of expression of the mutant gene Assuming that individuals are compared to individuals with the greatest degree, Only control vs. TS proband). The result is the first Indicated by a strategy, and the second strategy is to test a larger set Was also discussed if more information could be obtained. Adjust Bonferroni adjustment α value to an appropriate value. Given in the table (ie multiple comparison of subjects in mutually excluded categories) for).   ANOVA analysis was performed on three of three, two of three, one of three, one of three, And a large number of consecutive rows across 4 groups where 0 of 3 markers are present To determine if there was a significant linear decrease in the mean of the Performed using a trust (Dunn and Clark, 1995). Tukey test can be performed on any Each group score was analyzed to determine if α = 0.05 was significantly different from each other. Incorporated. To evaluate the rate of variation due to three dopaminergic genes Have markers for different behavioral scores simultaneously for all three genes Using 1 for those with no marker and 0 for those without a marker The analysis was performed. r^TwoIs the percentage change for each gene, and all three genes About r^TwoGave a total of. This means that for each specific behavior, all three The total percentage of variation explained by the gene was provided. result   For the total set, the number of subjects in the four groups of subjects, the average age, and Gender is shown in Table 35. The average age of TS probands is expected to be lower than the other groups, This is the case. Male to female ratio of TS proband and relatives of TS is higher than non-TS group Is also expected, and so is this case. However, the processed gene All were autosomal and the sex ratio itself was not expected to be a factor. To study this In addition, we found that in the presence or absence of different markers for gender, A power analysis was performed. There was no significant difference.   Taq A1 allele of DRD2 gene. Unaffected controls vs. unaffected Cases versus affected cases. TS proband, with chronic tics TS proband, with chronic tics TS proband without, and D in four groups of controls_TwoA1 allele The child morbidity is shown in Table 36. In both cases, control (23.5% and 36 .9%) to A1 allele prevalence in TS probands (415.% and 41.7%) There was a significant progressive increase by the Mantel-Haenszel linear chi-square.   Unaffected control versus unaffected disease for polygenotype sets P-value for cases vs. affected cases and for significant associations for the total set In, D_TwoTable 37 shows the results of determining the prevalence of the A1 allele. Most of the manic symptoms Significantly associated (p = 0.00024), 28.7% of cases without manic symptoms vs. symptoms Compared to 52.2% of patients with no allelic mania. 21.2% of the roll. Other significant changes are, in order, rebellious behavior, sexual behavior, ADHD -R, Schizophrenia, ADHD, Chick, Major Depression, and Act, For Total Set , Sexual behavior (p = 0.0007), stir (p = 0.0008), schizophrenia (p = 0.0016) and mania The most significant association was with disease (p = 0.0017).   D2A1 carrier vs D_TwoA statistic about A2A2 carrier average. Many behavioral evaluations Since it includes a continuous score, D_TwoCarry A1 allele (D_TwoA1A1 and D_TwoA2A2) or No (D_TwoTest the average of these scores for all subjects based on A2A2) Doing was also helpful. The results of the subjects in the multi-genotype set were Shown in Table 38A by decreasing constant values. Significant behavior in the total set All p-values are shown in the last column. Significant fluctuations are, in order, ADHD, mania, ADHD-R, action, Tics, rebellious behavior, schizophrenia, and sexual behavior. Three for the total set Further fluctuations, stuttering, compulsive behavior, and somatization were also significant. these Most remained significant when controls were not considered (hail 38 -B). By comparing the results of using all three dopaminergic genes together, Table 38-C lists significant results for controls and TS probands for the offspring set I do. Here, the actions are ranked highest, followed by mania, ADHD, and Schizophrenia, compulsive behavior, and rebellious behavior. D2A1 allele (D2A1 / D2A 1) Homozygosity gives higher average behavior score than heterozygosity (D2A1 / D2A2) All behavioral scores to determine whether these two groups The mean was tested. Mean is heterozygous for all variances except tic score The homozygosity was lower than that. This significant alcohol only for three variations, There was classroom, and reading.   Taq B1 allele of DβH gene. Taq B1 allegation in fluctuating psychiatric disorders Denko. 60.8% of 148 non-Latin American whites tested carry the DβH B1 allele. I had. 52.9% excluding alcohol, drug, and tobacco abusers or addictions Carried the B1 allele (Table 39). Prevalence of B1 allele using alpha of 0.05 There was a significant increase (p = 0.012) for 70.5% of 352 TS probands. Eliminate TS probands to determine if the severity of TS plays a role (TS The need for treatment of any aspect of the toll is moderate), moderate (requires treatment) Certain aspects) and severe (TS causing symptoms that cause great difficulty in life) Some aspects of the spectrum, Comings and Comings, 1985). To ease B1 vs. 54.3% for moderate to 72.1% for moderate and 72.7% for severe There was an increase in the prevalence of progeny. Moderate B1 allele prevalence The rate was significant at p = 0.0071.   The prevalence of the B1 allele was 73.1% (p = 0.01) for 78 subjects with ADHD. 9), and 73.1% (p = 0.012) for 104 smokers. B in other groups Prevalence of one allele does not increase significantly over control Was. When the association between the B1 allele with TS and smokers has no Bonferroni correlation However, such a correlation could inappropriately increase type II mistakes. (Rothman, 1990). B1 / B2 homozygosity in three grades of TS Posthoc analysis of B1 / B2 heterozygosity vs. 37.1% of relief of TS symptoms, moderate 49 5 and 62% of severe cases were B1 / B2 heterozygous (Mantel-Haenszelh linear Power = 6.25, p = 0.012).   Unaffected controls, unaffected cases, affected cases. Polygene Results on the prevalence of the DβH Taq B1 allele in 319 subjects in the set The results are shown in Table 40. ADHD is about 47% of controls for substance abuse or no ADHD. .1%, 70.6% of symptoms for no ADHD, and 81 for symptoms with ADHD The B1 allele prevalence of .9% was most significant (p = 0.0001). Other dominant actions Fluctuations are, in order, learning, class, ADHD-R, rebellious behavior, tics, mania, alcohol, Reading, substance abuse, sleep, stir, and compulsive behavior. Total set of The results were again most significant and similar to ADHD. Only men in the total set Sleep was most significant (p = 0.00005), followed by ODD (p = 0.002) And ADHD (p = 0.005).   T stats about B1 career vs B2B2 career. Table 41-A shows multiple genotype sets Shows the results in the case where is limited to control and TS proband. Other only significant Behavior was class (p = 0.029). The significant results of the total set are shown in Table 41-B. Rebellious behavior, sleep, ADHD, and reading were significant at α = 0.05. B1 Homozygous for alleles (B1 / B1) Heterozygous than heterozygosity (B1 / B2) These two for all behavioral scores to determine whether The means of the two groups were tested. Regarding any behavioral variation of homozygous versus heterozygous There were no significant differences.   10/10 genotype of the DAT1 gene. Different D for all sets of tested subjects The frequency of the AT1 allele is shown in Table 42. To simplify the analysis, Tourette's symptoms 10/10 genotypes for groups and autism, and different categories of behavioral disorders Was compared to the prevalence of 10 / x or x / x genotypes. Of 91 controls Of these, 37.4% had 10/10 genotypes. This is 52.3 for 241 TS probands % Increased. There were no significant differences in palliative, moderate, and severe TS won. Of the 36 subjects with autism, 58.3% were 10/10 (p = 0.031) . Results for TS probands and TS relatives were significant even after Bonferroni correction. Testing for 10 allelic variation gave comparable results (last two columns of Table 42).   Unaffected controls, unaffected cases, affected cases. 319 coats Table 43 shows these results for the multi-genotype set of samples. Variable with the highest chi-square The movement is embodied, and 21.1% of individuals without 10/10 Troll, 46.8% of TS probands, or relatives who do not have a physical problem, 60.3% Was a proband or relative of TS who had a problem of incarnation. The other dominant change is Alcohol, ADHD-R, major depression, depression, compulsive behavior, general Cheap, and mania. Significant for a reasonably large total set of 357 subjects The results are shown in the last column of Table 43. The major differences are rebellious behavior as a significant change, Sexual behavior, reading, and the addition of ADHD.   Mean T-statistics for 10/10 genotypes versus non-10 / 10 genotypes. When the total set is tested, Mobilization and major depression showed significantly higher averages for 10/10 genotypes (Table 44-A). There was no significant variation for all subjects in the polygenotype set . Only results for controls and TS probands for multi-genotype sets The results are shown in Table 44-B. This is the set used in the three additive effects tests . Here, the following changes were significant in order: general anxiety, major depression, ADHD-R, ADH D and alcohol.   Comparison of all three dopamine genes. Studied across all three genes Table 45 shows the results of each of the behavior scores. This group consists of all three Tester (group 1), 2 of 3 (group 2), 1 of 3 (Group 3) and 0 of 3 (Group 4). 4 gene groups The co-morbidity showing the most significant straight line associated with was ADHD (p = 0.0002). example For example, the ADHD score of a subject that inherited three of the three was 30.04, and 2 of the three The inherited subjects were 24.74, 3 of which were 20.42 and 3 of which were 14 Was .07. Group 4 mean (0 of 3) is the mean of both Group 1 and Group 2 Significantly lower than the score, and the mean of Group 3 was significantly lower than County 1. next The most significant were stutter scores -1.17, 1.06, 0.94, and 0.46 (P = 0.0002). The scores for rebellious behavior in groups 1-4 were 5.04, 3. 91, 3.38 and 1.93 (p = 0.0023). Each about behavioral disorders The scores were 4.08, 3.05, 2.87, and 1.93 (p = 0.0023). Other significant Fluctuations were tics, compulsive behavior, mania, alcohol, and general anxiety. The remaining behavior was not significant, but 16 of 20 were the same as lower genetic burden It showed a progressive linear decrease. The results are similar when using the whole polygenotype set. But moderately less significant.   To test these relationships in more detail, the most significant behavioral score, AD HD into 8 groups showing all possible combinations of markers for the 3 genes (Table 46). This was an increasing and decreasing trend. Similar background of tic score Also shown. These results are similar for the four gene categories and Significant for the same variation.   The result is somehow driven by an unidentified aspect of the control Test subjects (probands and relatives) with TS to test for The analysis was repeated using only Higher p-value results with narrower scores Nevertheless, ADHD, ADHD-R, somatization, and major depression are significant at p <0.05 And behavior, rebellious behavior, and mania were slightly significant at p <0.07. example For example, the ADHD score values for Groups 1-4 are 29.9, 26.1, 23.0, and 22.9, respectively. (P = 0.01); behavioral scores were 5.1, 4.0, 3.8, and 3.2; The anti-stress behavioral scores were 3.8, 3.3, 2.9, and 2.7. About more significant behavioral changes Table 47 shows the results of the evaluation of the rate of change in the above. Generally, the resulting DRD2 gene It was the most variable. Variability between 3.0 and 7.6% for key actions related to TS Was described by three dopamine genes.   In this study, genetic alterations that could be due to ethnic backgrounds or other similar disorders An attempt was made to evaluate. This includes: 1. All specimens are non-Latin American He was Caucasian. 2. ADHD, drug, alcohol, and tobacco abusers / dependencies About the proband and the relatives used for the TS proband and relatives. Was evaluated by the structuring means used. This is the control that owns the behavior being studied. Ruled out. The dramatic effect of this is that the total set Variability in the prevalence of the D2A1 allele in To 23.8%, and fluctuations in the number of eligible controls indicate different behaviors About from 67 to 40. 3. Many subjects Tested to avoid Type II mistakes. Thus, for the DRD2 locus, 484 Of the subjects were studied in the total set, and 319 were tested for the polygenotype set. Specified. 4. All subjects should have the same structured outline of psychiatric symptoms based on the DIS. Essentially applied. TS is a complex spectrum disorder (Comings, 1995d, Comings, 199 0) and that the D2A1 allele is a single dichotomous diagnostic entity (TS or TS (But not), rather than likely to be strongly associated with some actions but not others. Allows for the testing of a number of different behaviors. 5. Behavior to be tested With a chance for a very wide range of scores, a TS proband, having a TS or Has no TS relatives, and includes control. 6. Inadequate control The results were also analyzed without controls for evaluation. 7. individual May have a greater degree of genetic burden, so the purpose of a proband with Inclusion that is not a rejection. 8. Large family of types used for related research Rather than a focus on the population of many more seriously affected probands. here Non-probands are often more palliative. 9. Two in phenotype Test of the effects of the above gene combinations. In this case, the Taq A1 allele of the DRD2 gene Gene, Taq B1 allele of DβH gene, and 10/10 genotype of DAT1 gene . To achieve this, all three genes are tested in the same set of subjects. Specified.   Dopamine D2 receptor gene. D2A1 allele in TS proband versus other groups. As shown in Table 36, for the total set, 41.7% of TS probands and 35.0 of TS relatives %, 28.8% of relatives without TS have the D2A1 allele. This progress is p = 0.038, which was significant. The results of our control (26.9%) 714 non-Latin selected to exclude call and drug abusers / addicts 25.9% of the total number of American controls were distinguished from the prevalence of the D2A1 allele (Coming et al., 1996e). Our prevalence in TS probands (41.7%) also The proband of the total number of 432 TS subjects genotyped by the inventors It was virtually distinguishable. These results are consistent with a role for the DRD2 gene in TS Does not specify which part of the behavior spectrum is primarily affected. Check this To determine, we have three groups-controls without behavior in question, D2A1 alleles in cases without and with behavior Tested the morbidity,   20 distinctions associated with impulses, compulsions, addictions, sensitivities, anxiety, sleep, and learning behaviors Each symptom cluster was tested (Tables 37 and 38). (The 21st person has a double evaluation of ADHD Including). Variations significantly associated with the D2A1 allele include sexual behavior, stuttering, compulsive behavior, Schizophrenia, mania, ADHD-R, tic, ADHD, action, rebellious behavior, alcohol abuse, learning Habit and sleep problems. All other behaviors showed the same trend, but significant Was not. For the total set, the results were the two most significant actions (stutter and Sexual behavior) and the least significant behavior (phobia). Manic behavior is multi-relic Most significant for gene set chi-squared study, ranked high in table . This is consistent with our studies of behavior in relatives of TS probands, and Suggests that it shows the highest form of expression of the Gts gene (Comings. 1995d).   The lack of a correlation between the presence of the D2A1 allele and the severity of tics indicates that only TS probands When tested, the results were consistent with those of Devor (1992) and Gelernter et al. (1994b). I However, tic scores were significant when controls and non-TS relatives were included . In addition, if the case was statisticated by other behaviors, the D2A1 allele Correlated with lots of   Dopamine β-hydroxylase. Moderate prevalence of DβH Taq B1 allele However, 352 TS probands (70.5%) outperformed 148 controls (60.8%). Was significantly higher. Other subjects with significantly increased prevalence of the B1 allele The only group was smokers, 73.1%.   Significantly correlated with the DβH B1 allele in a multigene set of 319 subjects Thirteen variations, in order, are ADHD, learning, class, ADHD-R, rebellious behavior, tics, mania, Alcohol, reading, substance abuse, sleep, stir, and compulsive behavior . However, some of these (especially borderline significant: alcohol, drug abuse) , Stuttering, compulsive behavior), the prevalence of the B1 allele is And higher in probands and relatives without action than relatives Suggested that p-values were driven less frequently in controls. This Except for the addition of somatization and major depression, and the insignificance of stuttering, The same was true for a large total set of 5 subjects.   For polygenotype sets, the prevalence of the B1 allele in controls is It is in the range of 46.9-56.5%. Rows with both polygenotype and total sets ADHD, when the average of the dynamic score is tested for controls and TS probands Class, rebellious behavior, and sleep were significant. Our research is based on rebellious behavior. Motion was consistently significantly more associated with the B1 allele than with behavioral impairment.   To test the potential role of the DAT1 gene, we tested DRD2 and dβH As with genetic studies, the prevalence of 10/10 genotypes was determined by differences in controls. We compared the behaviors, TS probands, and relatives of TS subjects. This is the embody , Alcoholism, ADHD, major depression, compulsive behavior, general anxiety, mania, sexual behavior, And co-existing woodcutter behaviors, including rebellious behavioral disorders, were significantly correlated with numerous variations. Indicated.   These results indicate that a clear physiological link was associated with the 40 bp repeat allele of the DATI gene. While supporting the results of Gelernter et al. (1994a) showing efficacy, our results also indicate Suggests that psychopathology correlates with 10 alleles rather than 9 alleles. This This means that in all behaviors that showed a significant effect, progression in the frequency of 9 genotypes This is further supported by the finding that there was a behavioral decrease. For example, about embodying And the frequency of the 9 alleles increased from 0.37 to 0.29 in controls. Yes Relatives decreased to 0.29 for relatives who did not, and to 0.20 for relatives with embodyment, while The frequency of the 10 alleles increased from 0.54 to 0.70 to 0.77 over the same group. The frequency of the 10 most common allele is still higher in the presence of different sets of behavioral symptoms. It is interesting that it seems to increase further. One possible explanation is the 9 pair An allele is an intrinsically normal allele, and 10 alleles have one or more Increased frequency through selection due to correlation with the enumerated behavior of You.   All three dopaminergic genes. To study additive and declining effects, We show that relatively seriously affected TS probands, their relatives, and controls. , Obtain DNA samples in a large number of Genotyping was required. This was done with 319 samples. Two Stra One of the strategies was an empirical assumption and offered more power. First Strategy Includes testing the entire multigene set, which is not possible to increase potency. Most affected relatives were included. The second strategy is control and TS proband To test sub-parts of a multigene set consisting of only This means It provided the broadest score and, depending on the severity, provided a larger dichotomy. Both techniques give positive results, but the latter provided more effectiveness. result Indicates a linear decrease in the score for all but four actions tested. From a subject carrying three of the three markers, two or three of the three The test progressed to subjects having one and three out of three.   We have proposed that TS and ADHD are basically the same genetic disorder (Comings and Comings, 1984; Comings and Comings, 1987a; Knell and Comi ngs, 1993; Comings and Comings, 1993). These three dopaminergic genes The two most significant behaviors when children were combined were ADHD and ticks Provide confirmation of this hypothesis at the molecular genetic level. Significance with other actions The strong correlation is that they have constructed a spectrum of genetically related behaviors. Just in case I support. Assays for other genes are less affected by dopaminergic genes. Can help with phenotypes from the point of view. Birds affecting serotonin levels The putphan 2,3-dioxygenase gene is one example (Comings et al., 1996d). ). Evidence that exceeds the linear additive effect of the three genes (ie Is not found).   When behavior is most significantly associated with these three genes, all three markers ADHD was tested in more detail by listing all possible combinations. This These results were also consistent with additive and declining effects. Data shows three genetics The addition of offspring is a range of clinically significant scores from no diagnosis of ADHD to unclear diagnosis. It was shown that it could match the box. Has all three markers without symptoms of ADHD One or two subjects with three markers with clear cut ADHD There are still a few analytes that do not have any Give. Therefore, the choices for TS and ADHD are other than those involved in these disorders. Allelic variants of the genes of   Not all behavioral scores indicate the degree of this association with each of the eight combinations. did. To show this, the results of the same type of dichotomy are shown in Table 46 for tic scores. Show. Again, a proximal and significant decrease in tic scores across different combinations Small, but positive for the D2A1 allele but DβH B1 and DAT Subjects negative for the 10/10 genotype were significantly better with an average score of 5.0. Showed a discontinuity. This is a statistical anomaly due to a relatively small number of subjects in each group. Or the DRD2 allele is stronger in tics than other genes Suggestions for efficacy need further study. Research on the DRD2 gene By itself, it showed a significant correlation with tic severity.   Stuttering, just below ADHD, was ranked higher than it was originally The finding of the present invention suggests that stuttering is another symptom of the Gts gene. I support. These observations indicate that these behavioral disorders are entirely related to psychiatric factors ( In contrast to the generally held assumption that the To acts and rebellious behavior. No one suspects critical role of competitive reproduction Not a genetic factor, but if the reproductive bear or environmental factors are not wrong, act And may play a major role in rebellious disorders.   Percentage of variation due to the dopamine gene. Phase relationships using multiple linear regression analysis The calculation of the numbers shows the variation of the behavior for these three dopamine genes. Percentage evaluation was enabled. For all three genes, this is a change in the ADHD score. Dynamics ranged from 7.6% to stutter fluctuations of 1.3% (Table 47). Three genes To get an estimate of the relative importance of^TwoCombines values across all behavioral variations did. This suggests that the relative importance of the three genes is significant for DRD2, DAT1, and DβH The genes were shown to be in a ratio of approximately 3: 2: 1, respectively. The conclusion is that D For the RD2 gene, r represents eight behaviors (act, mania, schizophrenia, class, tic, O D, ODD, and phobia) and for the DAT gene Indicates that r is valid for three variables: depression, general anxiety, and alcohol abuse. Supported by the fact that For the DβH gene, r The three that are not significant and have the highest values are ADHD, ODD, action, and reading. , And learning disabilities. These results also indicate that different genes and The concept that combinations play a role in how phenotypes appear Provide support (Comings, 1995a). For example, all three genes are almost Equally involved in ADHD and ODD, but in behavioral disorders, involvement is DRD2> DβH> D AT1. For learning and reading, the order is DβH >> DAT1> DRD2 is there.   Chronic tic concordance in identical twins is less than 100% (Price et al., 1985 ), So the rate of variation (about 10-20%) is due to environmental factors. DRD2 and DβH The Taq polymorphisms used in genes are characterized by sequence changes responsible for functional alterations in the gene. No, but only in linkage imbalances with functional mutations, These assessments are probably underestimated (ie, the functional mutation itself is tested If it is, it can be higher). Ultimately, these assessments are All cases, controls, and probands with or without TS The average is shown. For example, 41 or 14.5% of 282 cases have a stuttering problem 43.7% have behavioral problems. By the subject who actually asks the question The rate of change is probably much higher.   These results are consistent with the polymorphism and multifunctionality of these disorders. These three The relatively low rate of variability due to the number of genes Standard linkage, despite significant involvement in unaffected and affected cases Why analysis is ineffective and how sensitive this association approach is to multiple genes Provide insight into                                 Example 7               Dopamine D1 receptor gene in addictive behavior Method   The three groups tested were the Tourette syndrome (TS) group, the smoking cessation group, and the pathological bet. It was a bounty. Subjects in all three groups restricted to non-Hispanic whites did.   TS group. This group includes controls without alcohol or substance abuse, Most of these TS probands are severely affected by multiple related behavioral disorders (Coming s, 1995b; Comings, 1990a), and the relatives of a TS proband. TS and everything Everything that met the DSM-IV diagnostic criteria was personally interviewed. TS group Controls include TS proband's fitness and step parents, Subjects with medical disorders, and professional and non-professionals It consists of hospital staff. Both TS subjects and controls are (Comings et al., 1966f; Comings, 1995b; Comings, 199). 4b; Comings, 1994c; Comings, 1995a).   Behavioral score. Each control and TS proband or relative should be -Schedule (Robins et al., 1981) or DSM-III-R (American Psychiatric Asso ciation, 1987) Write a questionnaire about the extent of the disorder based on the diagnostic criteria. Was needed. Symptoms were grouped into 23 different quantitative variables and attention deficit Active disorder (ADHD) (2 scores), alcohol, drugs, compulsive behavior, learning disability, reading Writing problems, gambling, mania symptoms, phobias, panic attacks, rebellious behavior, behavioral disorders, elementary school Academic problems in smoking, sexual behavior, schizophrenia, somatization, depression, sleep disorders, general The number of symptoms related to severe anxiety, stuttering and tics was assessed. These behavior scores The questions used were described in detail elsewhere (Comings, 1995a; Comi Comings, 1994b; Comings, 1995b; Comings et al., 1996a; Robins et al. 1981; Comings, 1995c). The rationale for testing comobrid gehavior The rationale is similar to that described in Example 2.   Some of the symptoms particularly relevant to this study were tobacco, alcohol, drug use, Related to eating and gambling. "No" or "Yes" to 18 questions Alcohol score, which is the final argument of the answer, comes from the MAST test for alcohol use (Comings, 1994b; Comings, 1990a). Drug score is related to substance abuse / addiction Related diagnostic interview schedule (Robins et al., 1981; Comings, 1994c) Based on a "No" or "Yes" answer to the 9 questions based. Strange smoking The number says, "You have tobacco, cigars or pipes every day for more than a month Have you ever smoked? " Where "yes" is 1, and "No" was counted as 0. The variables for shopping score are: Based on the final argument answering the question: "You have ever met your need Have bought items beyond your real need to buy like ? You have run into financial difficulties by buying more than you can afford Have you ever been? You've ever exceeded your net income, Have you used up your full credit card balance? You are the sky ever Have you ever gone shopping to fill your emptiness? You get happiness Do you shop for? Have you ever got things without paying is there? ". "No" responses are counted as 0, "Occasionally" responses are 1 And the “often” response was counted as two. The betting score is Severity involved in gambling previously described as gambling score (Comings et al., 1996e) Derived from nine "yes" or "no" questions related to. Obsessive Feeder Review The price says, "Have you ever considered your own compulsive feeding?" Based on a "yes" or "no" response to the question.   Smoking cessation group. The second group consisted of individuals attending a smoking cessation clinic. These tests Their own independent set of bodies and controls are responsible for DRD2 inheritance in smoking. Previous studies of the role of offspring have been described in more detail (Comings et al., 1996a). Honcho In the textbook, the variable for smoking assessment is the number of cigarette packs smoked per day. Average number. Controls include alcohol, tobacco, and other drugs. All types of drug abuse were excluded and screened.   Pathological betting. The third group is based on previous studies of the role of the DRD2 gene in pathological gambling. Coming of coming sick betting. Details and evaluation of patient confirmation are detailed elsewhere (Comings et al., 1996e).   Genotyping. To test the DRD1 gene, we tested the A in the 5 'UTR. Utilizing the Dbe1 polymorphism consisting of changes from to G as described previously (Cichon et al., 1994a) PCR^TMTested by procedure. The marker for the DRD2 gene is TaqIA It was a 1 / A2 polymorphism (Grandy et al., 1989).   Statistical analysis. In the TS group, the average behavioral score was calculated for subjects with different genotypes. Samples from the SPSS Statistical Package (SPSS, Inc., Chicago, III) Comparisons were made using the NOVA statistical program. Tukey analysis for more than two groups Was tested for significant individual differences between any individual groups. Predicted progressive increase in mean of different scores across different genotypes In some situations, a linear ANOVA is Used by setting command = 1. Based on the results of the ANOVA analysis, Chi-square analysis was performed to determine the residuals associated with the highest average behavioral scores in three different groups: A comparison was made of the frequency of transmission. The first is a control without any action to be tested. Made of Controls also had to fulfill one or more questionnaires So determine if a particular action was or was not present in the control Was possible. For TS group, both control and subject The presence or absence of such behavior is described in a previous study (Comings, 1995b). Based on the two-fold breakpoint. Controls without the specified actions Called the role. The same binomial break points indicate that TS probands and their relatives are divided into two groups ( (Without specific actions and those with actions) Made it possible. These groups are referred to as without and with, and And a third group. The forward-looking hypothesis is that a certain genotype If there is a significant association, the frequency of this genotype across these three groups And should increase gradually. Without and with The use of groups in cases may indicate the likelihood that genotypes may be increased in TS subjects. Controlled. Because it was associated with an action other than the one being tested. Departure The authors note that there is an incremental increase in the frequency of genotypes across these three groups Therefore, the linear chi-square test (Mantel in the SPSS Statistical Package) -Haenszel test) was used. Results show a linear increase over the three groups We also assume that the frequency of the genotype tested is Need at least 20% higher in the accompanying group than in the unaccompanied group Was. As in the study of dopaminergic genes in TS (Comings et al., 1996f) In addition, regression analysis calculates the percentage of variance of different behavioral scores explained by a particular gene. Has been found to be useful in determining This provides r, and r^TwoIs Provides that the ratio of the variance of a given quantitative trait is explained by that gene did.   Correction for multiple analysis. Significantly because 23 different behaviors were tested in the TS group It was necessary to make adjustments at various levels. Α of 0.05 is too free, while 0.05 / 23 Or an α of 0.002 was considered too conservative. Therefore, 0.05 / 10 or 0.005 Was selected. A study of the smoking cessation group using the forward-looking assumptions has Results and are involved in testing for single variables (packs smoked per day) And an α of 0.05 was used. Finally, the test for morbid betting is only a comparison of genotype frequencies. Was used, so an α of 0.05 was used. result   TS group. The allele frequency of the DbeI polymorphism for the control (n = 63) was 1 0.34 for the allele and 0.66 for the two alleles. TS proband The allele frequency for (n = 227) was 0.37 for one allele, and It was 0.63 for the biallele. There were no significant differences (χ^Two= 0.4 3, d.f. = 1, p = 0.51). Inheritance of DbeI polymorphism for control and TS groups The type distribution is shown in Table 48-A. 11 genotypes, 4.9% of controls and 1 of TS group Was present in 7.5% (χ^Two= 3.75, d.f. = 1, p = 0.053). 11 or 22 genotypes The difference in the percentage of those with a difference was 41.3% in the control and 57.3% of TS probands. This was significant (χ^Two= 5.08, d.f. = 1 , P = 0.024).   In a previous study of the TaqI A1 / A2 allele of the DRD2 gene, a broad range of quantitative Score is highest for 12 heterozygotes, for 22 homozygotes Showing an intermediate score and the lowest score for the 11 homozygotes was It has been observed all the time. Based on these studies, 12 The percentage of heterozygotes was assayed. These results for the TS group are shown in Table 48-B . 19.2% of 73 controls were 12 heterozygotes, while 3 of 345 TS probands 5.3% were heterozygotes (χ^Two= 7.19, d.f. = 1, p = 0.0073).   The interaction between the DRD1 and DRD2 genes was determined by the DRD1 DdeI 11 or 22 allele. Homozygotes for offspring and heterozygotes for the DRD2 TaqI A1 / A2 allele The assay was performed by assaying the proportion of subjects that were somatic. Each figure is 17.9% for trolls and 33.2% for TS probands (χ^Two= 5.71, d .f. = 1, p = 0.016).   The association between DdeI genotype and 23 quantitative trait variables was tested by ANOVA ( Table 49). α = 0.005, there was no significant one. The p-value for (a) was 0.0096. Of a score of 7 with a p-value of <0.20 5 is addictive behavior (alcohol use, smoking, compulsive eating, gambling, and shopping) G) related. Those with 11 genotypes had the highest scores. For example For alcohol use variables, those with 11 genotypes have 12 genotypes 0.23 for those with a genotype of 22 and 0.42 for those with 22 genotypes Had an average score of 1.30. Of all 23 variables, those with 11 genotypes It had the highest mean for all variables except learning disability and somatization.   Then, based on these results, we determined that the control, 11 inheritances for different behaviors across 3 groups with and without accompaniment It was tested whether there was an increasing increase in type frequency (Table 50). Linear The increase is significant at α ≧ 0.05, and the frequency of 11 genotypes in the group without There were three actions that were at least 20% higher in accompanying cases than in . In order of significance, there were gambling, alcohol use, and compulsive shopping. For example, for a gambling score, the prevalence of 11 genotypes indicates that From 4.6% for trolls to 15.5% for non-gambling cases, betting It increased to 33.3% for the case with the Expo problem (p = 0.0009). ≧ 0.05 α , Three additional variables (drug use, compulsive eating, and smoking) are: All related to addictive behavior.   Univariate regression analysis (Table 51-A) shows two behaviors (gambling and alcohol use). Was significant at p ≧ 0.005. At α of ≧ 0.05, four additional variables are compulsive Eating, smoking, tics, and reading skills. The next most significant action is Shoppi Was R for DdeI polymorphism^TwoBased on the DRD1 gene, 3.6% of variables, 2.8% of alcohol score, 1.9% of compulsive eating score, and Contributed to 1.6% of smoking scores.   Testing for potential interaction of DRD1 and DRD2 genes by multivariate regression analysis Prior to this, we used univariate regression analysis based on TaqI A1 / A2 polymorphisms. Therefore, the effect of the DRD2 gene was first tested. Has 11 and 22 homozygotes of DRD2 Subjects were counted as 1 and 12 heterozygotes were counted as 2. α = ≧ 0.005, the DRD2 gene has rebellious behavior, behavioral disorders, compulsive eating, smoking, gambling, And ADHD (Table 51-B). For α ≧ 0.05, a further variable is Mania, stuttering, obsessive-compulsive, and schizophrenic behavior. r^TwoBased on the value, Taq  Heterozygosity for the A1 allele was 4.2% of the 3.8% of disability variables, 4.1% of eating score, 3.3% of smoking score, and gambling Calculated for 2.9% of the core.   Multivariate regression analysis shows that r is the DRD1 gene for gambling, compulsive eating, and smoking And DRD2 genes were significant (Table 51-C). these For each, the results are additive, resulting in the combination of the DRD1 and DRD2 genes. When combined, calculations were made for 5.9 to 4.8% of these score variables. Al Summarizing the call score, 11 genotypes of the DRD1 gene have significant effects Showed that the effect of the DRD2 allele in this group was not significant.   The additive effect of the DRD1 and DRD2 genes was also tested using univariate regression analysis. did. Here, a sample having both the DRD1 Dbe11 genotype and the DRD2 Taq A12 genotype was identified as 3 , One with any genotype as 3 and any Were also counted as 1 (Table 51D). a ≧ 0.005 significant These variables include gambling, smoking, compulsive eating, rebellious behavior, ADHD, behavioral disorders, delusions Obsessive-compulsive, mania, and alcohol use.   The additive effects of the DRD1 and DRD2 genes also indicate that DRD1 DdeI 12 or 22 and DRD2 TaqI 11 or 22 (none); DRD1 DdeI 11 or DRD2 TaqI 12 (no Or DRD1 DdeI 11 and DRD2 TaqI 12 (both) Three groups were tested using linear ANOVA. α ≧ 0.005, which is There were no variables, so the variable obsessive-eating, eating Smoke, rebellious behavior, ADHD, behavioral disorders, obsessive-compulsive, mania, and alcohol behavior variables Showed a significant progressive increase.   The additive effect of the DRD1 and DRD2 genes is also the DRD1 Dde11 genotype, or D Linear for the frequency of the presence of either or both RD2 Taq A12 genotypes The test was performed using chi-square (Table 53). These variables are significant at a ≧ 0.005, and The mean for the unaccompanied group is less than for the unaccompanied group. Also 20% higher, mania, alcohol, obsessive-compulsive, behavioral disorders, schizophrenia, sexual behavior, strong Compulsory feeding followed by major depressive episodes. About the variables of alcohol use The result is compulsive eating and mania.   Test with genotype of DRD1 DdeI 11 or 22 between control and TS proband Because there were significant differences in body proportions, we also 11 or 12 inheritances across 3 groups, with and without trolls Assays were performed for the percentage of subjects with the pattern. The following variables are significant at α ≧ 0.05 And at least 20% higher than without Average (gambling, alcohol use, and elementary school issues).   Smoking cessation group. The frequency of the DdeI 1 allele in 61 smoking controls was 0.35. Yes and 0.34 in 177 smokers (Table 48A). Control smell 4.9% had 11 genotypes, compared to 17.5% of smokers (χ^Two= 5. 88, d.f. = 1, p = 0.015). In control, 39.3% had 11 or 22 remains Smokers accounted for 66.1% of those who had the epidemic (χ^Two= 13.45, d.f. = 1, p = 0.0002).   For the DRD2 gene, 26.2% of controls had 12 genotypes On the other hand, smokers accounted for 42.8% (χ^Two= 5.69, d.f. = 1, p = 0.017). Conte For roles, 24.1% had both DRDI 11 or 22 and DRD2 12 genotypes. Of smokers, 44.5% (χ^Two= 8.25, d.f. = 1, p = 0.0041).   The variable tested in the smoking cessation group was the packs smoked per day. All controls were behavioral questionnaires (same for smoking used in TS group) (Including questions), you have smoked tobacco, cigars, or pipes. These controls and those with drug or alcohol abuse Could be excluded. These individuals constituted a zero pack / day group. . Subjects in the non-smoking group smoke 1 to 11/2 and 2 to 21/2 packs per day Divided into things. (If you only smoke at least one pack per day, No subject smoked less than one pack per day as approved in the study. won). The results for the DRD1 gene are shown in Table 54. Test with 11 genotypes Body proportions increased from 4.9% to 16.4% and 18.0% across these three groups Ta (χ^Two= 5.14, p = 0.023). Of subjects with either 11 or 22 genotypes The percentage increased from 39.3% to 61.8% and 68.0% across these three groups Χ^Two= 12.87, p = 0.00033). Subject heterologous for DRD2 TaqI A1 / A2 polymorphism Conjugation rates increased from 26.2% to 34.5% and 46.3% across these three groups (Χ^Two= 7.99, p = 0.0047). Homozygous for DRD1 11 or 22 and The proportion of subjects that are both heterozygous for the DRD2 TaqI A1 / A2 allele Increased from 24.1 to 34.5, 50.4 across these three groups (χ^Two= 23.48, p = 0.0001).   The interaction of the DED1 and DRD2 genes for smoking was also Tested using a regression analysis (Table 55). This is because the DRD1 gene and DRD2 gene When marked by these polymorphisms, they were shown to contribute almost equally to each other. Those combined were calculated for 10.5% of the variance of the pack / day variable.   Pathological betting. Unlike TS and non-smokers, sick betting groups have their own core Did not have a set of controls. Therefore, for comparison purposes, the TS and Combine the smoke cessation controls to form the entire control group, and , Used for morbid betting. 14.1% of bettors have DRD1 DdeI 1 conflict Homozygous for the gene (χ^Two= 5.39, p = 0.020), 55.8%, and Homozygous for either 11 or 22 genotypes (χ^Two= 6.75, p = 0.009). For the DRD2 gene, 45.7% of stakers had a TaqI 12 group (χ^Two = 18.61, p = <0.0001). 23.3% of bettors have DRD1 11 or 22 genotype and DR It had the D2 TaqI 12 genotype.   Dopamine D in the range of psychiatric disorders₁And D_TwoMany studies showing interactions between Despite the research, potential associations between genetic variants of the DRD1 gene and behavior or Lack of research to test potential interactions between DRD1 gene variants and DRD2 gene Existing. The present inventors have proposed a variant of the DRD1 gene, or DRD1 gene and DR Additive effects of the D2 gene may also play a role in these actions. Showed interest. We selected the DRD1 DdeI polymorphism (Cichon et al., 1994a). . Because PCR^TMBased on a small number of alleles Because it was common in the group. Previous studies of the DRD2 gene had more than one Since the value of testing for the interaction of different genes has been The association between the variant and the potential additive effect of the TaqIA polymorphism of the DRD2 gene was tested. To minimize racial effects, only non-Hispanic whites were studied. Opportunity In order to minimize the effect, we set out three different groups of subjects (of which By testing two of them have their own set of controls) We considered any findings to be duplicated.   Alleles and genotype frequencies. Allele and genotype results are shown in Table 48A. You. For the DRD1 variant, the DdeI 1 allele in controls and subjects Were actually the same. 3 groups (TS proband, smoker, and better) , The allele frequencies were 0.37, 0.34, and 0.35, respectively. . For the TS and smoker control groups, the frequencies were 0.34 and 0.35, respectively. there were. Many reports of related studies in psychiatric disorders report that controls vs. specific Limit themselves for comparison of gene frequencies in subjects with disorders . A similar limitation is that the DRD1 gene plays a role in any of these disorders. Suggest that was not. However, because the genotype involvement can be different, Regardless of frequency similarity, we also tested genotype frequency. this is, Significant increase in prevalence of 11 genotypes and TS outbreaks in smokers and gamers There was a significant increase in border lines (p = 0.053) in the edge. TS origin 0.024, 0.0002, 0.009, and And any alleles for all four groups with p-values of 0.0001 And there was a significant increase in homozygosity. The latter three are <0.5 / 4 Used a Bonferroni corrected α of 0.0125.   Alleles and genotype frequencies for the Taq A1 allele of the DRD2 gene are tabulated. See 48B. Based on these results, in the present study, we found that A1 / A2 The proportion was tested. In TS probands, smokers, betting people, and the entire subject population, The results were 35.3, 42.8, 45.7, and 40.0%, respectively. TS, smoker, you And for all controls, the results were 19.2, 26.2, and 22.4%, respectively. there were. In all four groups, the prevalence of A1 / A2 heterozygotes was 0.0073, 0.0 17, subject than in controls with p-values of <0.0001 and 0.0001 Was significantly higher in In three of the four groups, the results were Bonfellow Two-corrected α ≧ 0.05 / 4 or 0.0125 remained significant.   The above results indicate a significantly negative heterozygosity for the DRD1 allele. Association and a significantly positive association with heterozygosity for the DRD2 allele The ream was shown. To test for potential interactions between DRD1 and DRD2 genes If we are not heterozygous for the DRD1 allele (ie , 11 or 22 homozygotes) and DRD2 alleles Divided together. Since these genotypes were optimized for both genes, Groups were designated as both. The second group (designated either) was DRD1 11 or 22 homozygous. It consisted of either zygotes or DRD2 heterozygotes. Third group (Designated as neither) was heterozygous for the DRD1 allele, and DRD2 There were 11 or 22 homozygotes for the allele. Table 48C shows these results. Show. The proportion of subjects present in both groups was TS proband (33.2) versus TS control (17.9) was significantly higher (p = 0.0041); smokers (45.5) versus smokers Significantly higher (p = 0.0041) for control (24.1) and all subjects (34.3) vs. all controls (20.8) were significantly higher (p = 0.0033) . Subject proportions in both groups did not increase significantly for stakeholders (23.3) Was.   TS group. The first preliminary study of the potential role of the DRD1 gene in behavior was identified in the TS group. And conducted these studies and studied more than one behavior, so these results are more detailed. Shown in We first identified 23 different groups of behaviors in different DRD1 genotypes. Were compared using ANOVA. 5 out of 7 actions with p-values less than 0.2 Was addictive (alcohol use, smoking, compulsive eating, gambling, and shopping) Ng). The alcohol use variable was the most significant (p = 0.0096), while α ≧ 0.00 5 was not significant (see methods). All of the quantitative traits shown in Table 49 , And 14 of the remaining 16 variables have the highest averages for 11 homozygotes. did. The average score in 22 homozygous pairs was higher than in 12 heterozygotes Often high, while the relative magnitude of the score for 11 vs. 12 heterozygotes was In the body TS group, homozygotes for 11 alleles became 22 alleles Showing greater association with elevated scores than homozygotes Was.   Based on the results of ANOVA, we have the following: Case, the proportion of subjects with 11 genotypes in the paired group was tested (Table 50). At α † <0.005, three actions (gambling, alcohol use, and shopping) G) were all significant. For gambling, this percentage ranges from 4.5 to 15.2, 35.2% (P = 0.00095). All 6 significant traits at α † <0.05 are addictive Sexual behavior.   Similar results could be obtained using univariate regression analysis, with the results for the DRD1 DdeI 1 allele Those that are mozygous are counted as 2 and have a genotype of 12 or 22 Was counted as 1. Gambling and alcohol use variables are significant at α <0.005 (Table 51). Univariate regression analysis for DRD2 gene (where A1 / A2 B) was counted as 2 and homozygosity was counted as 1). The trait was significant at α <0.005 (Table 51B). These are addictive behaviors (compulsive Eating, gambling, and smoking).   Using multivariate regression analysis, both DRD1 and DRD2 There were only three traits to give (gambling, compulsive feeding, and smoking) (Table 51C). same The same results were obtained using univariate regression analysis. Let's say that we have 3 in both groups And count in any group as 2 and then none Counted as 1 in group (Table 51D). In this specification, gambling, smoking, The p-value for and compulsive feeding was <0.0001.   In order to assess the magnitude of the score, we consider none, any, Or the means for those in both groups were tested by ANOVA (Table 52 ). As used herein, eight traits (including compulsive eating, smoking, and alcohol use) Was significant at α <0.005. Means were consistently higher in both groups. Final tests are performed across untreated controls, with and with groups , DRD1 11 homozygotes and / or DRD1 A1 / A2 heterozygotes It was a test of the proportion of certain subjects (Table 53). Alcohol use and compulsive eating α ≧ 0.005, significant among the 8 traits. For alcohol use, the percentage is , Increased from 23.9 to 46.9, 70.6 across the three groups (p = 0.00005).   These combined results indicate that DRD1 genetics in numerous addictions and other behaviors Was consistent with the role of offspring and the additive effects of genetic variants on DRD1 and DRD2 . Both homozygosity for both DRD1 and the two alleles were Score higher than conjugation, while in the TS group Homozygosity has given a strong association with a number of traits.   Smoking cessation group. We have identified these findings in a totally different group of subjects. To determine if either could be replicated, we asked smokers to Individuals from previous studies of the role of the DRD2 gene were used (Comings et al., 1996a). This All subjects in this group smoke at least one pack of cigarettes per day and Attempts to stop smoking were unsuccessful. As discussed above, a group Smokers have a lower incidence of DRD1 DdeI 11 genotype and 11 or 22 genotypes. , Showed a significant increase. Exploring the correlation between DRD1 gene and smoking in more detail To test, we tested the quantitative traits of packs that smoked per day (Tables 54 and 55). Control to smoke 0 packs per day, and 1 day Smokers who use 1 to 11 パ ッ ク 2 packs and 2 to 21２2 per day Subjects with a DRD111 genotype of 4.9 to 16.4 or 18.0% across three groups of smokers In body proportion, it was progressive and significantly increased (p = 0.023). TS group In contrast, for smokers, 11 or 22 heterozygous groups had more significant results Gave. Therefore, the percentage of homozygous subjects is 0 packs per day (control From 39.3 for smokers using 1 to 11/2 packs per day 61.8 per day, up to 68.0 for smokers using 2 to 21/2 packs (P = 0.00033). The proportion of homozygotes transmitted to the DRD2 A1 / A2 allele Increased from 26.2 to 34.5, 46.3 across these three groups (p = 0.047 ). As in the TS group, the effects of the DRD1 and DRD2 genes are additive. Therefore, both The proportion of subjects in one group was 24.1 to 34.5, Increase to 50.4 (p = 0.0001). Addition of DRD1 and DRD2 genes in smokers To further test the effect, we set the daily packed variable to be multivariable. Tested using quantitative regression analysis. There is a comparable effect on both genes, And combine them for 10.5% of the variance of packed variables per day Calculated.   Gambler. As discussed above, the betting player has a higher DR than all controls. D1 In the percentage of subjects that are 11 homozygotes or 11 or 22 homozygotes A significant increase in the proportion of subjects that are DRD2 A1 / A2 heterozygotes There was an increase. Unlike TS and the smoker population, these effects are Was not additive. Because the proportion of subjects in both groups was It did not increase beyond the roll.   Heterozygosity. Average score for range of behavior in different numbers of subjects The present inventors have observed that genetic variants at the DRD1 and DRD2 genes It suggested that it could show momentum. Interestingly, the effect is on two genes It was the opposite. Therefore, the DRD2 gene TaqI A1 / A2 heterozygote Heterozygotes for the DRD1 gene were normal Score. We have found that both polymorphisms are DRD1 and DRD2 genes. Assume that there is linkage disequilibrium with other mutations affecting offspring function (Comings Et al., 1991). The mechanism of action of this apparent heterozygosity advantage / disadvantage is unknown It is. The opposite effect on the two genes is that they Due to the fact that it has the opposite effect, or simply due to chain imbalance It is also unknown whether they are due to opportunity variability in other related variants. is there. The results of the present invention show that the polymorphic DRD1 plus DRD2 gene Show the role of the legend. The inner part of polygenic inheritance plays a key role in gene combinations In contrast, this study also illustrates the significant effects of allele combinations. Show.   Importance of subject confirmation. Role of the DRD1 gene across three independent sets of subjects Addition of DRD1 and DRD2 genes in two independent sets of subjects The significance of the effect can be ascertained. Initial diagnosis is alcoholism or drug addiction Preliminary studies by the present inventors on the subjects for which the reasons were confirmed showed that the role of the DRD1 gene and DRD1 gene and DRD2 gene in some but not all forms of drug and substance abuse Supports the additive effect of the gene. This is not an unexpected aspect of polygenic inheritance. No. DRD1 and DRD2 genes were isolated for less than 6% of a given trait variable. And the combined trait variables account for less than 11%. Their moderate effects could be easily crushed by differences in subject confirmation . For example, a number of receptor abnormalities include dopamine, serotonin, cannabinoi Drug, nitric oxide, nicotine-like muscarinic, GABA, etc. Seems to be very involved. Diagnosis of Tourette syndrome depends on the presence of motor tics Dependent, and dopamine plays a role in regulating muscle movement. Therefore, TS Drug abuse or other addictive behaviors concurrently affected in In the group of subjects identified based on any type, It is expected to contain more gene deletions.   The importance of testing for symptoms that differ from the diagnostic level. These and previous studies (Comi ngs and Comings. 1987b) is related because of the broadness of a single dichotomous category Suggests that studies may result in significant loss of performance. For example, a TS subject Chicks, from individuals with some mild tics and no other problems A destructive set of mori, ADHD, compulsiveness, behavior, anxiety, mood, substance abuse, and learning disabilities It can range up to individuals with a combination. Certain genes contribute to TS, This gene is particularly associated with stuttering, and if stuttering is present in only 20% of cases, The child's role can be lost in the comparison of control versus all TS probands, but Raku, in comparison of control without stutter vs. TS proband with stir Is detected. This concept was particularly important in this study. In the TS group, DR Behavioral variables significantly associated with the D1 gene were involved in addictive behavior. This This suggests that animal studies also have a role for DRD1 in addictive traits, and that There appears to be an opportunity to discover why they were replicated in three different groups of subjects. Was.   There are some warnings about this study. DRD1 DdeI polymorphism is a neural basis Because of the change, we believe that dopamine D₁DRD1 inheritance affects receptor density Assume that there is linkage disequilibrium with mutations in or near the locus. Relation The frequency relationship of the study is based on the fact that the result is a hidden race or This could be due to ethnic stratification. The present inventors have studied non-Hispanic white An attempt was made to minimize this by limiting it to humans, By replicating the findings in three independent groups, this is a possible theory It remains clear. The second potential problem (especially in the TS group) is that of 23 different quantifications It is a test of a characteristic trait. Compensate for this by using a very conservative α of ≧ 0.005 did. When testing the combined effects of the DRD1 and DRD2 genes, many p-value is less than 0.001 and less than 0.05 / 23 or 0.0022 full Bonferroni correction there were. In addition, addictive behaviors (alcoholism, compulsive eating, gambling, shopping Clusters of significant results around (and smoking) provide some internal consistency. Provided. The final warning is that the DRD1 11 allele is highlighted in the table for the TS group. However, 11 or 22 homozygosity was highlighted in the table for the smoking group It is. However, as shown in Table 48, the homozygosity of 11 or 22 was Were significant across the study groups. A feature that all three groups generally have is DR Reduction in average score for D112 homozygotes, and DRD2 A1 / A2 heterozygous There was an increase in the average score for coalescence. The confirmation bias discussed above Also, why homozygosity for one allele is more severe in one group of subjects May be important, while homozygosity for both the 1 and 2 alleles Plays a role in deciding what could be more important.                                 Example 8      Effect of treatment with enkephalinase inhibitor and releaser   In this example, Lewis (a preferred multidrug) and Fischer (a preferred non-multiple drug) Species) d-phenyl in release of dopamine into the nucleus accumbens of both rats Alanine (another enkephalinase inhibitor), Tyr-D-Arg (an enkephalinase Release) and naltrexone (a narcotic antagonist) Test for efficacy. Lewis and Fischer rats were divided into two groups: acute County and chronic group. The chronic group has daily doses of three drugs: 500 mg / kg d-phenyl Alanine (DPA)-1-5 mg / kg Tyr-D-Arg (TDA), and 1-2 mg / kg Naruto Lexon (NX) (DuPont, Wilmington, DE) is given every morning for 18 days. Day 19 Initiate microdialysis sampling for either chronic treatment or acute You. Change drug combination: administer all three; any two optional Combination; each drug alone. The acute doses of the three drugs are as follows: DPA = 50 0 mg / kg i.p., TDA 5 mg / kg i.p., NX i.p. 2 mg / kg.   Microdialysis method. Seven days before the study, all rats were assigned stereotaxic coordinates (bregma related). ) With a microdialysis probe in the left Acb, pentobarbital sodium hemp Surgically implanted under drunk (50 mg / kg): A + 2.0, L1.2, and V-8.0 (skull From)). The probe is coaxial design, and 0.5mm outer diameter stainless steel Build from pipes (Small Parts Company, Roanoake, VA). Each probe is 2mm Exposed dialysis membrane, which has an outer diameter of 250 μM (Spectra / POr hollow cell Loin fiber, MWC05000, Spectrum Medical Industries, Los Angeles, CA) It essentially covers the vertical extent of the Acb.   Rats collected for dialysis. Probes as determined by in vitro studies About 3.9% dopamine (DA), 3,4-dihydroxyphenyl vinegar 4.1% for acid (DOPAC) and 3.2% for homovanillic acid (HVA). Immediately after implantation, probe fusion begins and lasts for the duration of the study. Electrochemistry Measurement was performed using two LC-4C detectors (Bioanalytical Systems, Inc., West Lafayette). , IN) combined with a carbon working electrode on double glass with both + 0.7V vs. Ag / ACl reference electrodes Do it regularly. One electrode is used for DA detection and the other is used for DOPAC and HVA detection. To use. Dialysis samples are started after the animal has recovered from 20-24 hours of surgery I do. Collect dialysis samples to DA dialysate level, DOPAC and HVA stable is there. The three 20 minute baseline pre-injection samples are then collected. Any chronic Prior to injection, the predialysate is analyzed for baseline volume. This baseline Establish chronic injections before commencing chronic injections. Drug combination for acute rats Occurs before collection at fixed, predetermined intervals, which varies from study to study. Six All 20 minute samples are collected over 2 hours after drug administration. Chronic and steep Rats in both sex groups also had walking and stereotaxy from the start of the study. Observed about Ip's behavior. After all harvests have been completed, standard histological analysis is performed. Perform in all rat brains to confirm probe position.   Self-selection. Drug combinations for self-selection in Lewis versus Fischer rats Other studies on the effects of alcohol also include alcohol, cocaine, sugar solutions, and marijuana. And DPA alone and TDA and Determine the effect of the combination of NX and NX. DPA inhibits GABA transmission activity Inhibition of central tegmental GABAergic activity by a combination of and DA Should be the most powerful in significantly increasing The use of NX It seems to prevent rucol induced intoxication.                                 Example 9                   Association of DRD2A1 allele and body fat percentage Method   Obese subject. The purpose of the study was to predominate but not inherently morbid obesity The purpose was to obtain a subject group consisting of subjects. Women with a fat content of 34% or more , And men with a fat content greater than or equal to 28% were considered morbidly obese.   Control. Controls are twin parents from the Minnesota Twin Family study Consists of These are based on having an 11 or 17 year old twin, Of all socio-economic and educational groups, Shows a good set. The results of drug abuse assessment are still beneficial in twin controls. Because they are not available, we used the "unscreened control" These are listed as. Subjects in obese samples may also be subject to drug abuse. This is comparable to the subject for the presence of obesity A comparable control was made.   result. The obesity group consisted of 91 subjects (76 females and 15 males). 60 women Had 78.9% morbidly obese and the remaining 16 or 21.1% were overweight, The fat percentage was less than 34%. 12 or 80% of men are morbidly obese and the rest 3 or 20% were overweight but had less than 28% fat. Not morbidly obese Were too small for separate phylogenetic analyses, The two groups were combined for analysis.   DRD2 D in obese subjects versus controls_TwoTable 56 shows the prevalence of A1 alleles. Show. For all men and women, 67.0% of obese subjects had a 32.3% screen D compared to controls without_TwoHad the A1 allele (χ^Two= 32.9 5, p = 0.00001). This figure shows 980 screens reported in the literature since 1990. Substantially identical to the 32.9% figure for unlean Caucasians (Table 57) . The prevalence of 68.4% is significantly higher than for controls. About DAT1 gene Table 58 shows the results. In contrast to the DRD2 gene, There were no significant increases in 10/10 genotype prevalence in full subjects.                                 Example 10              Analysis of other polygenic alleles for detection of RDS   Tryptophan 2,3 dioxygenase. Deficiencies in serotonin metabolism and Abnormalities in both blood serotonin and tryptophan levels are It has been reported in psychiatric disorders. Tryptophan 2,3-dioxygenase (TDO2) is a tryptophan to N-folmyl kenurenine Is the rate-limiting enzyme for the degradation of Functional variants of this gene have Observed increase or decrease in both serotonin and tryptophan in Can be explained. Four different polymorphisms of the human TDO2 gene have been identified. Relation Studies show that one or more of these polymorphisms and Tourette's syndrome (TS), attention deficit hyperactivity 2 shows a significant association between dyskinesia (ADHD) and drug dependence. Intron 6^{G → T}Variant Was significantly associated with platelet serotonin levels. Bonfero only related to TS Bonferroni correction was significant (p = 0.005).   Subject. TS probands, TS family members, ADHD probands, 2/3 of autistic probands , And most controls are parents, relatives of parents, TS and the City o f Treated at another clinic at Hope National Medical Center (COH). TS, chronic luck Diagnosis of dyskinesia, or chronic vocal tics disorder, ADHD, and autism is DSM-II Based on I-R (American Psychiatric Association, 1987) diagnostic criteria. TS origin Is defined as a TS individual who considered medical treatment at this TSS-ADHD clinic. All origins Individuals and most of their relatives are personally interviewed and tested by D.E.C. did. 82% of probands had TS, while the remaining 18% had chronic motor tic disorder Had either harm or chronic vocal tic disorder. TS family members Yes With or without, she was the parent of the proband of TS. One-third of autistic subjects are Samamor e I came from Children's Hospital, Dix Hills, NY (J.S.). Each proband and them Asked relatives about the race and ethnic background of their four grandparents, and Only subjects where all four grandparents were non-Hispanic whites were included. all Signed informed consent and research from Institutional Review B Approved by oard. Smokers (Comings et al., 1996a), sick stakers (Coming s) Et al., 1996b), individuals with alcoholism (Comings et al., 1994), and drugs Individuals with dependence (Comings et al., 1994) have been shown to have DRD2 genes in these disorders. Derived from a role study. The choice and source of these analytes should be Write in detail in these manuscripts.   DNA samples from schizophrenic and depressed subjects were obtained from National Neurological Res. The subject's brain scan with these diagnoses at each Bank (V.A. Wadsworth Hospital, CA) Sample. Subjects with schizophrenia have chronic schizophrenia and usually Has a long history of hospitalization in a mental hospital. Depressed subjects experience suicide, and Has a history of chronic depression. Diagnosis of schizophrenia and depression requires at least two patients Based on consistent DSM-III or DSM-IIIR criteria by psychiatrist. Accompanying al Subjects with call addiction or substance abuse were excluded.   Control. COH controls are derived from four sources: a) CEPH (Centred 'Etude du Polymorphisme Humain) grandparents unrelated to family; b) adoption of TS patients C) thyroid cancer or endocrine of non-insulin dependent diabetes Medical examination subjects; and d) professionals, associate specialists, technicians, and maintenance workers Hospital staff, including the elderly. This broad range of controls allows for more limited Used to avoid potential choice problems when used. Endocrine Patient was selected as control. Because the conditions are easily Are both treated and cause minimal disruption to life, and Because they were at age and the patient basis was similar to the TS subject basis. All controls to exclude alcohol, drug and tobacco abuse Was screened.   PCR of mutant region of intron 6^TMamplification. PCR to amplify TDO2 target sequence^TMAnti Yes Was as follows: 10 mM Tris-HCl, pH 8.3, 50 mM KCl, 1.5 mM MgCl_Two, 0.0 5% Tween 20, 0.05% NP-40, 100μM each dATP, dCTP, dTTP, dGTP, 0.1μ M primer. This primer is no. 116 GAC ACT TCT GGA ATT AGT GGA GG ( SEQ ID NO: 5), and no. 117 GAA GTT AAA TCC ATG TGG CTC (SEQ ID NO: 6). Less than Was added: 0.5 U AmpliTaq (Perkin-Elmer, Foster City, CA), 1 μl ( 250ng) Genomic DNA. Perform the reaction with a PE-9600 thermal cycler (Perkin Elmer) or PTC. -100 programmable thermal controller (MJ Research, Inc., Watertown, MA) using the following protocol: 5 minutes at 94 ° C, then 30 seconds at 94 ° C. Cycle, 30 seconds at 60 ° C, 1 minute at 72 ° C, then 5 minutes at 72 ° C. Determine if amplification has occurred To determine, 10 μl of the reaction mixture was run on a 1.5% agarose gel in TBS buffer. Electrophoresis was performed.   Cloning and sequencing. Primers 116 (SEQ ID NO: 5) and 117 (SEQ ID NO: No. 6) PCR^TMThe product was ethanol precipitated and TE buffer (Tris Hcl 10 mM, EDTA (1 mM). Fragments are modified into Blue Script pBdT (Hoton and Graham , 1991). The 20 μl ligation reaction is as follows: 20 μl of 10 × ligation buffer (Boehringer Mannheim), 100ng each PCR^TMProduct, pBdT and 1 μl of T4 Contains gauze. This was incubated at 11 ° C. for 18 hours. Of the fragment The sequence was compared to the terminal primers T3, T7 and the internal primer nos129 GCT GAT. TTT CAG ACT GAG TGT G (SEQ ID NO: 7) and 130 CTA CAA ACA TAT TTA AAC ATA TG Using T T (SEQ ID NO: 8), Applied Biosystems, Inc. (Foster City, CA) Determined by a column determining device.   Denaturing gradient gel electrophoresis. No. 116 which is an oligomer of intron 6 (SEQ ID NO: 5) Between 117 and 117 (SEQ ID NO: 6) by PCR^TMAnd a 1359 bp fragment I got it. Digest the fragment with RasI and digest the 816, 470 and 60 bp fragments Brought. These are subjected to a 20-80% denaturing 6.5% acrylamide gel at 60 ° C. and 70 V for 16 hours. Electrophoresis for hours (Grey, 1992). PCR^TMWith 10 mM Tris-HCl, 50 mM KCl, 1.5 mM M MgCl_Two, 0.05% Tween 20, 0.05% NP-40, pH 8.3 in a buffer of 0.2 μM each. This was performed using a primer and 0.2 mM of each deoxy NTP. 20 μl PCR^TMProduct RasI digestion, 2.3 μl of 10 × re digest with digest to identify fragment size action I buffer (New England Biolobs, Beverly, MA), using 5 U of enzyme (in 1 μl) Overnight at 37 ° C.   BstI digestion. PCR above^TMFrom the reaction, a 10 μl aliquot was transferred to 1.5 U of the restriction enzyme BslI. And finally 1 × buffer (supplied by New England Biolabs. Beverly, Mass.) ) And digested overnight at 55 ° C. 10 of digestion products aliquots of 4% meta in 1 × TBE buffer (Tris-borate 100 mM, EDTA 1 mM) Electrophoresis on phor agarose (F.M.C.Products, Rockland, ME) gel at 100V for 1 hour Provided. The gel was stained with ethidium bromide. Three different size fragments Event was predicted. If the polymorphic site is G / G, the DNA is completely digested and And a 359 bp fragment. If the polymorphic site is A / A, 1032 bp Was undigested. The G / A heterozygote contains three fragments (10 32 bp, 673 bp, and 359 bp).   Oligonucleotide ligation assay (OLA). Used in OLA for G → T variants The oligonucleotides obtained are as follows: For G-specific oligomers , OLA-G CTA TTC TTA TCC CTC TTT TCT TAA- (HEO) 1 (SEQ ID NO: 9). T-specific orientation For the sesame, OLA-T ATA TTC TTA TCC CTC TTT TCT TAAT- (HEO) 3 (sequence number No. 10). It has one G-specific oligomer and the T-specific oligomer 3U hexaethylene added to the 5 'end to change the molecular weight of one oligomer Oxide phosphamide (Grossman et al., 1994). Common oligomers are , FAM-TATA TAT TAC GGT TTA TTA CCGT-PO4 (SEQ ID NO: 11), where FAM is Was 5 'carboxyfluorescein phosphoramidite (Applied Biosystem s, Foster City, CA). G-specific and general oligomers are formed by ligase reaction When ligated, the estimated two weights were 50.5 bp. T-specific and general When the different oligomers were ligated, the estimated weight was 56.5 bp. About the OLA reaction The reaction mixture consists of: 20 mM Tris HCl, pH 7.6, 100 mM KCl 10 mM Mg Cl_Two, 10 mM dithiothreitol, 1 mM NAD, 0.1% Tritou X-100, 10 nM oligomer. 10U Ligase (New England Biolabs) and 1 μl PCR^TM20 μl of each product Added to the reaction mixture. The reaction was performed with the following cycle using a PE-9600 thermal cycler. This was performed using a signaling protocol: 94 ° C., 20 cycles of 30 seconds, 54 ° C. for 2 minutes 30 seconds. 2 each Mix μl reaction with 0.5 μl deionized formamide and heat at 92 ° C for 2 minutes And denatured. All 2.5 μl on an 8% acrylamide gel in TBE and 8 M urea Filled and electrophoresed for 3 hours. The reaction product is analyzed using fluorescent staining primer Whether electrophoresis or silver staining with the pplied Biosystems DNA Sequencer It was identified by misalignment. The latter is double-stained, i.e. stains-all first, then silver Consisting of staining. Gels were prepared in 0.01% Stains-All (50% formamide pH 7.5) Eastman Kodak, Rochester, NY) in solution for 20-30 minutes, then 2% glycerol Decolorization overnight. The gel was then washed twice in 10% ethanol, 0.5% acetic acid, each time. And washed for 30 minutes. The gel was then run for 20-30 minutes with 0.1% AgNO_ThreeIncubate in solution Wash twice with deionized water, then 1.5% in 11 freshly prepared distilled water  NaOH, 0.01% NaBH_Four, Place in 4 ml of a 37% formamide solution. Band is 10-20 minutes Within 0.75% Na_TwoCO_ThreeStop using and with 5% acetic acid Fixed. Identification of G → T variants by DpnII digestion. The G → T sequence near 3 ′ is GATA there were. GATC is the recognition site for the DpnII restriction endonuclease. Three The 23 bp oligomer of 3 'was converted from the 3' immediate ATC sequence to a G → T variant as shown below. (The oligomers are underlined and the variants The two g sites are double underlined): 5'-TCA TTA ATC CTC TGG GTA TTG TA A ATG TGG ATT TAG GTT AAT GTA TTA TAT ATA ATG CCA AAT AAT GGC AGA TAA GA A TAG GGA GAA AAA GAA TTA-3 '(SEQ ID NO: 12), 5'-ATT AAT CCT CTG GGT ATT GT -3 '(SEQ ID NO: 13), 5'-TAG TCT TAT CCC TCT TTT TCT TA-3 '(SEQ ID NO: 14), This mismatch at position 3^TMSometimes its effect as a primer Spoil. The 5 'primer was chosen to provide a 92 bp product. G → T modification If the body is A, only a 92 bp fragment is present.   PCR^TMThe conditions for the reaction were as follows: 0.1 μM each primer, 0.2 mM each dNTP, 50 mM KCl, 10 mM Tris HCl, 1.5 mM MgCl_Two, 0.001% (w / v) gelatin, 1 80 ng of genomic DNA. PCR^TMCycles are 94 ° C for 4 minutes, 30 cycles of 94 ° C for 30 seconds, 5 cycles 90 seconds at 2 ° C, 120 seconds at 72 ° C; followed by 5 minutes to 72 ° C. The conditions for DpnII digestion are 10 μl PCR^TMProduct, 10 μl of 0.05 μl^-1DpnII; 1.5 μl 1 M NaCl, 0.5 M Bis HCl, 0.1M MgCl_Two, 10 mM dithiothreitol, pH 7.9; 3.5 μl H_TwoO, overnight at 37 ° C Met. The product was electrophoresed on 4% Metaphor agarose.   CCC CT repeat amplification. Oligos used to detect CCCCT repeats of intron 5 No. 166 5'-CTC TTA CAA TAG AAG AAA CCA TTT-3 '(SEQ ID NO: 15) and no . 167 5′-TCT CCT It was the reverse complement of CTC TTT CCC TTC CC-3 ′ (SEQ ID NO: 16). Increase Width conditions are 95 ° C for 5 minutes, then 30 cycles of 95 ° C for 1 minute, 50 ° C for 1 minute, and 72 ° C For 1 minute followed by 72 ° C. for 5 minutes. The final concentration of the reaction mixture was 50 mM KCl, 1.5 mM M MgCl_Two, 10 mM Tris, pH 8.3, 0.1 μM primer, 200 μM each dATP, dCT P, dTTP, 100 μM dGTP and 7-deazo-dGTP, respectively, and 0.5 μl template It was.   Identification of exon 7A → C mutation (Asn → His) polymorphism. PCR of A → C variant^TMamplification Primers for 5′-GCA TGG CTG GAA GAA CTC C-3 ′ (SEQ ID NO: 17) 5 ′ primer Primer and 5'-TCT TCC AGG CCT CTG GTC ATA T-3 '(SEQ ID NO: 18) 3' It was an immer. This generated 89 bp product digested at the C modification site with NdeI Resulted in 67 bp and 22 bp fragments.   Relevance studies. The approach used was for unrelated controls in the same racial group. To compare the prevalence of the various alleles in the proband with the allele. Bonferroni's collection α in Tables 59, 60 and 61 is 0.05 / 10 or 0.005 was. These studies were performed over a period of several years. New polymorphism Based on the identification, early studies on hundreds of subjects indicated that the variant If not significantly related to shape, the subject was not tested further. As a result Thus, the number of subjects studied varied for different variants.   Non-random allele association. Stage-specific because no pedigree research was conducted Haplotype frequency could not be determined. Therefore, the classical analysis of linkage disequilibrium (Lewontin and Kojima, 1960; Lewontin, 1964). Researched Tested the degree of non-random allelic association between the four different polymorphisms Estimated by inter-body pedigree, where two or more tests were performed on the same individual. all All subjects in all diagnostic categories are included in these analyses.   Analysis by special behavior. Dopamine D in TS_TwoReceptor gene DRD2, DβH In studies of the and DAT1 gene roles (Comings et al., 1996c), we We found that analysis by populations with different dynamic signs was a wonderful finding. This This indicates the prevalence of specific alleles in controls without the behavior in question, Tests were performed on probands with TS and relatives with behavior in question.   Serotonin and tryptophan levels. Platelet serotonin levels, seroto Techniques for analyzing nin / platelet ratios and plasma tryptophan levels Indicated elsewhere (Comings, 1990b). result   Control. Unrelated CEPH grandparents constituted 60% of controls. Duty Determine if our own control group will produce different results To this end, the frequencies of polymorphisms were compared across different groups.は Significant difference by analysis won.   Intron 6DGGE polymorphism. Polymorphism determined by polyacrylamide gel electrophoresis did. The results of the original intron 6DGGE polymorphism are shown in Table 62. Represents allele 2 The less frequent band was present in 12.1% of the 91 controls. This is 40 Of 27.5% of TS patients, 28.4% of 26 sick bets, and 10 of drug abusers Significantly in 50% of these and 37.5% of 8 subjects with depression who attempted suicide Increased. However, these numbers are small and we have a large number of subjects Before proceeding with his work, he wanted to identify the variants involved. Sequencing studies, 2 Identified two polymorphisms, a G → T variant and a second G → A variant, and identified two base pairs Split (Comings, 1995). We first use a ligation assay These variants are tested separately and then the modified primers and restriction endonucleases are A simpler procedure was developed using creatase (see Methods).  G → A mutant. Table 59 shows the results of the G → A variant of intron 6. 141 cons Of the trawls, only 3.5% carried the A allele. 10 tested Among the groups, only significant results at α = 0.05 were 10.4% in 299TS subjects (odds ratio 3 .15), and 10.6% had an increase in the A allele in the cousin of 151TS. All of these are valid at the Bonferroni-corrected p-values of 0.05 / 10 or 0.005. It was not intention.   G → T mutant. Table 60 shows the results of the G → T variants. 197 controls Of these, 15.7% possessed the T allele. It has ADHD (p = 0.048) Increased to 25/0% in 108 subjects with drug or multiple drug dependence (p = 0.016) Increased to 28.7% in 73 subjects, and with alcohol dependence (p = 0.049) Decreased to 6.1% of the 65 subjects. None of these are significant at α = 0.005 Did not.   A variant of either G → A or G → T. We consider that G → A or G → T The prevalence of the presence of typology was tested (Table 61). 135 cohorts performed in both experiments Of the controls, 17% carried either allele. This is ADHD (p = 0.028) 29.1% for 96 subjects, 70 subjects with drug dependence (p = 0.01) Increased to 32.9% and 29.9% for 271 subjects with TS (p = 0.005) Added. 6.3% reduction in 64 subjects with alcohol dependence (p = 0.03) . Only the TS result was significant at α = 0.005.   Exon 7A → C, 748Asn → His variant. The present inventors have found that the Asn → His variant Because it is a xon mutant and contains amino acids that are important for heme binding Expected to be useful. The C or His allele was 6.3 of the 48 controls. % And this form is associated with ADHD, autism, schizophrenia and TS There was little change for the subject and it was not significant.   CCCCT polymorphism. Salt at the 3 'end of intron 5 for all subjects tested The base length and allele frequencies in the CCCCT repeat region are as follows.   The 240 alleles and 240/240 genotype were much more frequent. analysis For 240/240 genes, frequency of 240 / non-240 and non-240 / non-240 genotypes It was compared with the type frequency. Of the 125 controls, 31.2% are 240 / non-240 or Carried the non-240 / non-240 genotype. The prevalence for other groups is substantially Identical, ranging from 22.1% to 30.5%, and significantly different from controls There was no.   Non-random allele association. Table 63 shows the non-LA among the four TDO2 variants studied. The results of a presumed random allele association are shown. All of the 1245 subjects were G → A And G → T variants were tested, but only 10 subjects showed A allele and And one heterozygous for the T allele and one TT homozygous Sex and A heterozygotes, indicating that both variants were on the same chromosome. You. Each variant allele is relatively rare, with 18.0% being T alleles. Yes, and both were 24.1%. These results show that these two adjacent The variants (2 bp apart) are on separate chromosomes and the observed distribution is independent It was no different from the chance combination of standing events. G → T and A → C variants Of the 312 subjects tested for both (Table 63B), heterozygotes for both There was no compatibility. For the complete set, only 7.4% have C alleles on the same chromosome Carried the gene (AC heterozygous at AA homozygosity). G → A and CCCC Of the 621 subjects tested for both T polymorphisms (Table 63D), only 6 had A And heterozygous for the non-240 bp CCCCT allele and one non- -240 / non-240 homozygotes were GT heterozygous. These distributions are by chance Unlikely, they suggested that they were on completely separate chromosomes.   Finally, 696 tested for both G → T and CCCCT polymorphisms (Table 63-E) Of the 169 240 / non-240 heterozygotes among the subjects, 80 (47.6%) Of the non-240 / non-240 homozygotes, 19 (70.3%) Or TT, and 10 (100%) of the TT homozygotes were non-240 / non-240 It was homozygous. This association is very significant (χ^Two= 421.07, p <0.0 0001), non-random allele association between non-240 CCCCT variant and T allele Showed a high degree of. This result indicates that at least 50% of the non-240 alleles Occurs on the chromosome chromosome, and at least 78% of the T alleles are non-240 alleles It suggests that it occurs on a gene chromosome.   Comparison by individual actions. Different behavioral scoring tools for A or T alleles Results are useful only for the presence of various phobias. (P = 0.043) with an average value of 2.89 for the results not associated with. For TS proband Control without phobia, and without phobia for TS probands When comparing the prevalence of any variant in relatives and relatives with phobia The result for phobia is the highest straight lineχ^Two(3.45) but not significant (P = 0.06). As used herein, any of 18.8% to 24.15%, up to 34.1% The increased prevalence of is greater than these three groups. If the individual's behavior is non- It is not significantly associated with the 240 bp allele.   TD02 polymorphism and serotonin levels. Data are based on platelet cell sero from previous studies. Available at tonin and blood tryptophan levels (Comings, 1990 b). Because some subjects are involved in both studies, different TDO2 alleles The level of platelet serotonin or blood tryptophan in subjects with offspring If there is any difference between the two, it can be determined. These results are shown in Table 64. Shown in For G → A variants, ANOVA analysis or Mann-Whitney non- G / A and A / A compared to G / G subjects by either There was no significant change in the serotonin / platelet ratio in the cells. GG or GT, TT FIG. 4 is a distribution of serotonin / platelet ratio values for these genotypes.   The range of values was similar, but the distribution was different from the normal distribution. G → T polymorphism G Many values are grouped in the range of 0.5 to 1.25, with values preserving the G genotype Was. In contrast, values carrying the T allele were rare in this range. There was also a 10.9 value borderline for the T allele group. Do not delete this border Mean, the mean value of the serotonin / platelet ratio will be the value carrying the T allele. Significantly higher (p = 0.003). If this value is excluded, the p-value is 0. It fell to 081. However, the T alleles are more appropriate for the Mann-Whitney nonpara It still had a significantly higher mean in the meter test. For CCCCT repeat polymorphisms, Serotonin / blood with higher polymorphism carrying the non-240 allele as measured With a proportion of platelets. However, the differences were not significant. Tryptophan level Was not significant for any polymorphism.                                 Example 11                            Addition of genetic association   PS1 gene polymorphism. Presenilin-1 (PS-1) polymorphism is located on chromosome 14 And has been associated with Harzheimer's disease. Smoker Reported that reducing the risk of developing Harzheimer's disease Of a series of 132 non-Hispanic whites who have been determined to have a tendency to use The subject's PS-1 gene was tested. The present inventors believe that this gene (genotype is 1/1 And 2/2) are significantly more frequently present in tobacco smokers (p <0.05), and significantly increased in the Michigan Alcoholism Screening Test (MAST) (P <0.01).   Subject genomic DNA was extracted from whole blood by standard procedures. PCR^TMMethod (Saik i, et al., 1988) in the separation reaction with 0.1 μM of each primer (5 ′ CAC CCA TTT ACA  AGT TTA GC3 ') (SEQ ID NO: 19) and 5' CAC TGA TTA CTA ATT CAG GAT C3 '(sequence No. 20) was used to amplify the target DNA. The reaction is first brought to 94 ° C, 5 Denaturation at 94 ° C for 30 seconds followed by a second step of denaturation at 94 ° C for 30 seconds. Kneading and extension at 72 ° C. for 30 seconds. Repeat the second step in 34 cycles And a final extension step at 72 ° C. for 5 minutes. 2.5 U of 199 bp amplification product System Digestion was performed with the restriction enzyme BamHI at 37 ° C. overnight.   The digested product was electrophoresed on a 10% PAGE at 150 V for 2 hours, and Stained with mubromide. Genotype generation of two fragments of 181 bp and 18 bp Care was taken based on the resulting restriction cleavage sites AC (Wragg et al., 1996).   ADRA2C dinucleotide repeat polymorphism. ADRA2C dinucleotide repeats on chromosome 4p Polymorphisms range from 179 to 193 base pairs. The human genome database for this polymorphism The source accession number is M94915. We have a series of 53 non-Hispanic This genetic marker was tested in white Caucasian drug abusers and The presence of an allele (≦ 181 bp) indicates a more severe drug use trend (cocaine, Use of fetamine and heroin) but severe Not found. The present inventors have proposed dinucleotide repeat alleles in the following manner. Genotypes were constructed from the gene: Homozygous for genotype 1 = ≦ 181 bp; gene Type 2 = heterozygosity (allele 1 ≤ 181 bp, allele 2 ≥ 183 bp), and gene Type 3 = homozygous for ≧ 183 bp. Genotype 1 increases the amount of money spent on drugs (p <0.01), increased age of amphetamine use (p <0.05), and heroin use Associated with an increase in the number of years (p <0.05). Conversely, high base pair alleles (genes Type 3) uses more alcohol in the last 30 days (p <0.01), alcohol Increased number of years of use (p <0.05), and the primary reason for seeking treatment Alcohol (but not drug) poisoning indications (p <0.05).   The human genome database accession number for this polymorphism is GDB: 196352. And the sequence is M94915. Subject's genomic DNA is collected from whole blood using standard procedures Extracted from PCR^TM(Saiki et al., 1988) were compared with 0.1 μM of each fluorescence in the separation reaction. Labeled primers (5'AGT GGG CAG GGC GGG GCA GGT 3 ') (SEQ ID NO: 21) and 5 Amplify target DNA using 'CGC TGC CTC CCT TCC ACC TGT TG3' (SEQ ID NO: 22) Used to The reaction was first denatured at 94 ° C for 5 minutes, followed by Second step of denaturation at 0 seconds, annealing at 57 ° C, 30 seconds, and extension at 72 ° C, 30 seconds did. The second step is repeated 29 cycles, and the program ends at 72 ° C, 5 The last extension step was in minutes. For gel analysis, each reaction was diluted to 0.5 μl. Amplified PCR (15 μL in 75 μL deionized water)^TMProduct, 2.5 μl mixture (2.0 μl l deionized formamide, and 0.25 μl ROX500 standard, and 0.25 μl Bluedoxtran dye) and denatured at 92 ° C for 2 minutes. Denatured sun Pull the sample to an Applied Biosystems 373 DNA sequencer (Gene Scan^TM) 6% PAGE The gel was then electrophoresed for 5 hours at 1500 volts and at a constant 30 W. Gel Pretreated and analyzed using an internal standard (ROX500). genotyper (ba Version 1.1) recognizes two peaks based on fragment color and size did. The assigned value is a picture that indicates that exact determination of the size of the allele. In minutes. Complete information about each sample is available from each gel file. The printed and compiled data is submitted for analysis.   We have identified a series of 64 drug abuser dinucleotide repeats in the PENK gene. The 3'-terminal CA repeats that were typographic were tested. We believe that high base pair conflicts Subjects who are homozygous for the gene (≥80 base pairs) have more significant severe He had alcohol dependence and drug addiction. High base pair alleles addiction Increased number of years of drinking (p <0.05), increased number of drug detoxification treatments (p <0.01), Increased years of drug use (p <0.05), increased frequency of drug treatment (p <0.05), and It may be related to the frequent use of methadone maintenance treatment (p <0.05).                                 Example 12                     PHENCAL^TMSensitive to treatment with                          Determination of allelic variants   Which RDS genes, and specifically which polymorphisms, suppress specific RDS behavior To determine if the individual is most susceptible to pharmacological intervention Potential candidates were tested for specific polymorphisms in the RDS gene and Assays have been performed to identify RDS behavior and / or have been disclosed herein. Provided for the pharmacological treatment using the composition to be prepared. Specific RDS genes or Is the presence of a gene polymorphism, the presence of RDS behavior identified by a psychological assay And / or RDS behavior in treatment with the compositions disclosed herein Can be evaluated statistically. RDS behavior suppressed by neurotrophic composition In contrast, the RDS gene polymorphism showing a statistically significant correlation (eg, p <0.05) is Thus, the diagnosis of individuals who are more likely to be successfully treated using a neurotrophic composition Identified as disconnected. Formulations of the components of a general RDS treatment composition are given in Table 4, And one or more of the listed components may include one or more of the RDS actions described herein. It is intended to be effective in treating individuals who exhibit In addition, Tables 6-16 Certain preferred formulations are preferred for the treatment of certain RDS behaviors disclosed herein. Include. How certain elements are identified as stimulants (such as cocaine), opium, See Table 17 for a schematic of whether it provides a reward induced by pain-killing hypnosis See also -19. Treatment combined with genetic diagnosis of RDS behavior Specific examples of the law are disclosed below:   Carbohydrate overeating or anti-obesity. Genetic implications for carbohydrate eating and successful treatment In view of this, we have today identified many probands as genotyping and PHENCAL^TM Providing the subject with 6 capsules per day of the formulation and measuring the weight loss for 90 days, Determine the carbohydrate glut diet score and the weight recovery over the next 6-8 months. This is for placebo. Extremely good improvements have been made on various genes during the study. If it occurs in a type, it is determined. For the study of obesity, we have the following: Genes and possibly others, and their respective polymorphisms (already PHENCAL)^TMDetermine for successful treatment with: D1, D2, D4, DAT1, DβH, COMT, MAOA (x), TD02, APO-D, Chromosome 2 marker, U CP-2, CNR1, GABAB3, HTR2A, HTR1A, and nNOS1a (see Table 5).   Protocol details: PHENCAL responds clinically as a function of genotype^TMand Limited variants containing nicotinate chromium salts   Research participants. Participants in this study were morbidly obese and had an ideal body weight of 13 Weigh between 0-180%, or have 34% body fat for women, and Men have 28% body fat. Patients are between the ages of 18 and 65. Patient, he They are excluded if they suffer from hypertension, diabetes, or other debilitating diseases.   Study design. This clinical trial is based on a matched placebo (Weider Nutriti 6 caps per day compared to on cap group, Salt Lake City, Utah) Le PHENCAL^TM(See Table 4 for general prescriptions and specific prescriptions See Table 7) for subjects receiving double blind placebo This is a double-blind-placebo-controlled study. This is 14 weeks It is an interim study. The first two weeks include increased intensive effects and blood screening Including DNA collection of stomach and salivary swabs and measurement with a weighing scale. Once the subject When you participate in a study and sign standard informed consent, The volume of the control lung is determined by the Collins Helium Dilution pulmonary functioning unit n E. Collins, Inc, Braintree, Mass) using a local lung laboratory Measured. The underwater test (replacement method) correlates strongly with hydrostatic weighing and Whitmore Volumeter (Whitmore Enter) with test retest reliability between 0.96 and 0.99 terprises, San Texas) (Ward et al., 1978). Commercial to detect Platform scale (Model 8850, Deteco Scale company, Web City, Mi ssouri) is calibrated to 1/10 of the pound and used to get the scale weight . In addition, we applied the Dual Energy X-Ray Absorptometry (DE & A) test And measure the bone density.   Within a two-week period during which all these studies are completed, subjects will have their genotype ( Except that this remains private until the study is prepared for analysis). The test results are provided and PHENCAL^TMOr of that matched placebo One of the pre-coded bottles containing either is randomly selected. Subject Consumes 6 capsules per day, 2 capsules 1 hour before breakfast, lunch and dinner Asked if you did. The manufacturer takes on the role of trustee, and Code before distribution. We are the research technician who distributes the product, or Specimen code is PHENCAL^TMOr one of the matched placebos I don't know. d-fenfluroamine or phenteramine alone or in combination No diet, unlike some other studies achieved either in combination Or exercise information is provided, and the subject is What program did you want during the test as long as you took the supplement (For a certain number of subjects, we consider "The Optimal Heal th Diet Plan (developed by Dr. Gilbert Kaats (San Antonio, Texas)) " Take Can be included). Subjects will visit the center weekly and receive another bottle of refill or Receive placebo and weigh. Testing period (capsule taking Subject completes body component testing. All data Is processed on a computer, and the University of Texas Health Science C Enter-Houston-San-Antonio, Texas Department of Computing Research Is analyzed. At the time of analysis, the trustee is required to transfer the code. Erasing the actual amount PHENCAL spent^TMAnd placebo is calculated from the self-report of the product use subject.   In this study, the primary outcome measure was the placebo or PHEN CAL^TM5 is a comparison of the average change in body composition change during the period. PHENCAL without chromium^TMAnd And chromium picolinate, chromium nicotinate, or a combination of the two Mu PHENCAL^TMIs evaluated. Average changes in body composition are based on genotype-based subpopulations. Are compared. Large numbers of haplota beyond all the genes tested above Ip is a standard gene multiple regression analysis applied by Comings described earlier. (By OBKIT for identification in genotyping)^TMchecking) .   Anti-smoking. Nicorest^TMBy applying the formulation, a large number of heavy smoke Kerr was genotyped according to the master plan of the present invention. The following NicorestTM According to the diet, 6 capsules per day (see Table 10) for 90 days, the results are shown below Measured in terms of: ease of stopping; withdrawal symptoms (including suppression); recurrence. this The data is evaluated for all the above genes. For a complete history of smoking, see Comi ngs et al. (1996) performed according to previous studies (O for identification in genotyping). NIKOKIT^TMchecking).   Detailed Protocol: Alcotrol as a Function of Genotype^TMAnd Cocotrol^TM.   The study included outpatients who were given anti-alcoholic and anti-cocaine formulations, The results are measured from the symptoms of early detoxification and no program regression, Includes relapse rates as measured by any regression of known drug selection (See Table 5).   Subject participation. In this study, all patients were Minnesota Multiphasic Person Using Quality Inventory (MMPI) and Blood Analysis Performed at Hospitalization (CBC / SMAC-24) And evaluate. No further blood tests will be done at the end of the study. This group is: Arco -Alcotrol^TMAlcohol-Placebo; Stimulant Abuser (Cocaine) -Cocotrol^{T M} Stimulant abusers-placebo.   Study design. Age, weight, gender, race, and BAL participation were And test with covariance where possible. In facilitating treatment within a patient, , Nurses, and subjects, data collectors,^TMAlso Is Cocotrol^TMOr provide information on receiving a matched placebo I can't. The dose is 2 capsules per day for each prescription and the divided dose is 1 Served in hours (see Tables 8 and 9). Test measurement   Skin conductivity level (SCL). The electrical properties of the skin can be used to assess emotional responses Has been widely applied. This technique is a complete measure of patient stress levels. Have a reliable proof (eg, degree of worry or anger). By itself, This is an indirect measure of the stress level in the patient. Scl, paroxysmal skin resistance The reciprocal of gender (GSR) is monitored by a micromhos (Edelberg, 1972) The conductivity level of such skin is measured. Sympathetic activity increases skin conductivity There is a correlation between the directional response and the anxiety response due to exercise. Therefore, in conductivity Reduced autonomic arousal is associated with reduced autonomic arousal (Luthe, 1969). Make these measurements To do this, attach the Autogen3000 to the middle finger of each patient's dominant arm and read Get a stake. Measurements are taken for each patient selected for the study at undetermined time. The patient does not notice that he / she was measured.   Clinical measurement. Physical (Clinical Instltute Withdrawal Assessment for Alc ohol co-occurrence (CIWA-A) (Shaw et al., 1981) and BESS notation are The primary measurement applied for each patient during the complete stay in this 28-day is there. Both Physical and BESS notations have been described (Blum et al., 1989). Those During the course of the change in treatment with factors of the clinical director, staff physician, And are monitored daily by the Director of Clinical Nursing and their observations are Discussed and coordinated to reach sussus. When joining , Each patient is assigned a baseline score value of 5. Respectively Day improvement or regression is described in a range of 6-10 improvements, and 0-4 regressions; 5 Does not show any change from membership status.   Determination of the message type. Each patient who visits the clinic is the SUDKIT^TMDNA saliva indicated by Used for liquid swab test. All genotypes, including medical directors, It remains hidden from staff. When the data is prepared for analysis, Genotype is Department of Computing Resource University of Texas-Houston / S Published only for statistical purposes to an Antonio. Gene to be tested Is D1, D2, D4, DAT1 (10 / 10.9 / 9), TDO2, nNOS1a, CNR1, GABAB3, HT2R, MA OA (X) and COMT.   Statistical analysis of the data. Alcotrol^TMAnd Cocotrol^TMThe effect of the treatment is placebo Are analyzed in combination for alcohol and stimulant abusers. most Importantly, we have found that treatment of stress response and functional genotype Evaluate clinical measurements, including Physical and Bess scores.   Protocol details: Hy in ADHD probands as a function of genotype research participants perGen^TM. The present inventor has applied the ADHD scale, TOVA test and CCPT HyperGenTM dual blind placebo control for ADHD children in patient diagnosis The Troll study is in the process of dosing in a 6 capsule per day formulation. The inventor They then compared the scores for the test before and after the test, and Correlate the results of different genes. The study was conducted in two regions (Texas and Tennessee) ADHD subjects in the diagnosis of outpatients. Subjects were tested with TOVA and ADHD scales. (Including Cull and Blum, 1997) and Wisconsin card sorting tests Is diagnosed by a psychological test. Officials said that the Axis II diagnosis exclusive psychiatric He has a negative background on various conditions. All subjects at the time of testing Not taking any medication and each subject has signed informed consent And agree to administer the capsules according to the protocol.   Study design. Subjects completed two complete studies (TOVA, Cull / Blum ADHD Call) and perform the task (see below), these are test-re-test Form a model. The first test is on day 0 (pre-test) and then again after 90 days (post-test) ). For between subjects, HyperGen^TMOr matched placebo One dose of 6 capsules per day (2 hours before breakfast, lunch and dinner) I am asked to consume in medicinal quantities. HyperGen^TMThe compositions of are shown in Table 12. this is Is a double blind placebo control study, and the manufacturer has completed the study Preserves precoding information that is sometimes provided to the statician. Pieces Neither the person nor the subject has information associated with the coded bottle.   Execution task. Two execution paradigms used to induce electrophysiological responses Do:   Spatial orientation. This is the Reaction Time Task (SOT), (Posner et al., 1988) The priming cues are present in the left and right visual fields. Reaction time Compare cases where they are intense and not available. Through comparison of reaction times Enables the evaluation of an individual's ability to smoothly switch attention between perspectives. In this study In this context, the challenge is to be more careful processing with more transformative control of attention. Built to allow for a more basic level of assessment, and a more automatic It tends to pack heavier at different stages (Defrance et al., 1993).   Indeterminate continuous execution. Uncertain continuous execution task (CCPT) is a modification of the classic theme And incorporates elements of both selective and sustained attention. The task is a careful process Analyzed to ensure quality of execution, indicating a more controlled stage of the thing. Alphabet letters appear one at a time in the center of the screen. Basically, individuals Is a particular letter order (eg, "T" if immediately followed by another "T"). The first "T" in the "T" pair serves as a warning cue, and the second: the target "t" By pressing the left mouse button (the right-handed group) against his dominant arm. Examine the response. All other characters are considered Distracters, which are subject It should be ignored. Basic calculations on data follow previous studies (Defr ance et al., 1997). Prefrontal cortex is most importantly involved in sustained attention and effort And is an important factor in considering the overall performance of this task, and And is very sensitive to administration of stimulants (Sostek et al., 1980).   Recording scheme. EEG with 28 controls connected to earlobes (A1-A2) as described State was recorded from the recording site (Defrance et al., 1996). One set of each stimulus presentation is 800ms caused by ec. EEG sampling from ERP is built: baseline A 100 msec pre-stimulus sampling used for acquisition is included at each time Was.   Data analysis. Basic analysis follows previous work (Defrance et al., 1997) and In general, it involves the evaluation of three parameters, each of which is a personal attention profile. It can vary according to the effectiveness of the processing. These parameters are: ERP components Potential, amplitude and symmetry (spatial distribution) (Defrance et al., 1997).   This study is based on the ADHD (HYPERKIT discussed at the beginning and described in this application).^TM HyperGen for the gene allele associated with^TMDue to Note that processing changes are noted. DRD2A1 allele, DβH B1 allele Gene, VNTR10 / 10 repeats of DAT1, and TDO2, MAOA (X) polymorphism and HTR1 It is at least expected that subjects carrying the A gene will respond very strongly.   Anti-violence and aggression. Relevance is related to schizophrenic and avoidance behavior Thus, "morbid violence" and dopaminergic polymorphisms (ie, DRD2 and DATI alleles) ) Are found during these actions, as shown in Tables 14 and 15. It is logical to evaluate the use of aggression formulations. This dose is standard 6 capsules per day for targeted placebo. The measurement of results can be determined by various probands. I.e., youth and prisoners) and quiet persons with common lower hostility Reduction in the number of non-motivational outbursts. Measure results at 6 months Associated with genotypes (see TEMPKIT) as discussed above in the intermission. In this study we used either of the formulations corresponding to Tables 14 or 15. I do. The study was conducted at Ford Youth Center in Learned Kansas with 40 confined young people. Implemented.                                 Example 13   Multi-additive related techniques for gene identification in multigenic disorders (M                    AA): Outcome of ADHD and co-morbidities   ADHD is the most common disorder, affecting most pediatric psychologists and psychiatrists. It is estimated to be present in 2-8% of more treated and school-aged children. ADHD A clear, organic, neurological, and / or genetic disorder There is evidence. Compared to controls, fathers of ADHD or hypersensitive children Have a degree of ADHD, alcoholism, and antisocial personality disorder (ASPD), and Mothers may find that high frequency ADHD, alcoholism, and “hysteria” or hysteria He has a personality (Morrison and Stewart, 1971; Cantwell, 1972). ADHD Children's siblings (Sib) have a high frequency of ADHD (Augest and Stewart, 1972; Paul) s et al., 1983; Weiner et al., 1977), particularly where one of the parents is ADHD or the child is the same twin In some cases (Hechman, 1994). In brothers versus half-siblings The ratio of these actions ranges from 2.0 to 5.2 compared to Matches the factor. Parental children with ASP are more likely to have ADHD, And had a significant increase in the frequency of temper tantrums (Cadir et al., 1978).   Most relatives of ADHD probands have 8% ADH compared to control relatives Had a D. Major depressive disorder, rebellious behavioral disorder (ODD), behavioral disorder, antisocial person Personality disorders, alcoholism, drug or alcoholism, anxiety disorders, (general (Including writhing disorders, including anxiety disorders) (Biederman et al., 1990). ADHD and mood disorders May share common familial vulnerabilities (Biederman et al., 1990) and have ADHD with disability May differ from the subtype of ADHD (Farone et al., 1993a), and Anxiety disorders (Hodge et al., 1986), and ADHD and learning disabilities (LD) (Farone et al., 1993) b) may be communicated independently in the family.   Deficiencies in dopamine metabolism have long been implicated in the pathogenesis of ADHD. Impairment of dopaminergic neurons in the limbic system (exposed area) is overactive, Responsiveness, poor response to stress and other impairments in rodents (Lemoal et al., 1976; Lemoal et al., 1991). Frontal lobe dopa just after birth Chemical destruction of minergic neurons generates animal models of ADHD in response to stimuli (Shaywitz et al., 1976; Shaywitz et al., 1991). Tourette failure with low level HVA (TD) detected in children with (TD) (Cohen et al., 1979k; Butler et al., 1979k). Low CSF  HVA was reported in children with ADHD (Shaywitz et al., 1979k), but CSF HVA and A positive correlation between hyperreactivity and behavioral disorder ADHD was also reported. Brain image Zing studies show defect in dopamine-rich striatum in ADHD (Comings Noble et al., 1994k), and hypofunctionality of the frontal lobe of ADHD and TD (Zam etkin et al., 1990). Studies were conducted on dopamine transporter or DRD3 It showed hyperreactivity in knockout mice with deleted offspring. Dopamine action Sex agonists have been used successfully in ADHD treatment.   The general hypothesis by the inventors is that ADHD may be dopamine, norepinephrine, serotype Additional effects of genes affecting tonin, GABA, and other neurotransmitters occur. Is a multigenic disorder. Some specific included genes Are the dopamine genes (DRD1, DRD2, DRD3, and DRD4 receptors -Gene, dopamine beta hydroxylase, and dopamine transporter); Norepinephrine (NE) and epinephrine (EPI) genes (ADRA2A and ADRA2 C receptor, PNMT, norepinephrine transporter, MAOA, COMT); Tonin gene (TDO2, serotonin transporter, serotonin receptor inheritance Offspring); GABA gene (GABA receptor gene GABRB3, etc.), and as yet unidentified Other genes.   The present inventors have identified three dopamine crops for ADHD and other co-diseased disorders. Utility genes DRD2, DBH and DAT (Comings et al., 1997b), 3 adrenals Genes, DBH, ADR2C and ADR2C (Comings et al., 1998a) and androgen Receptor gene AR, DRD2 and serotonin transporter gene HT The additive effect of T (Comings et al., 1998b) was tested. These studies are based on the following two The principle was demonstrated: First, the subject identified that at 0, 1.2, or 3 of these genes When divided into groups that represent the presence of an alteration, A progressive increase in the size of QTV, which is more significant than Studies show that this technology increases QTV scores and decreases QTV scores Phenotypes by genes that play a small or negligible role in And what could be used for the fixation of genes that play a role.   We have studied the additive role of all 29 different genes of ADHD. These principles have been extended. The present inventors considered this as a Multiple additive Associatio ns (MAA) technology. We tested the hypothesis for the MAA technique. Different QTVs can vary widely in the range and size of the score, and we have The regression correlation (r) and the percentage of variance described (r^Two) And analyze the results And plot comparisons of size effects of various genes across different QTVs Enable. The following are the hypotheses and apps incorporated in some of these studies. Roach.   MAA techniques for studying ADHD and other behaviors include dopamine, serotonin, Modification of genes affecting lupinephrine, GABA, NMDA and other neurotransmitters Variant allele Inherited from parents is hypothesized to be the most psychiatric disorder (Blum et al, 1990; Comings, 1996a; Comings, 1998a). In this report, The candidate genes we selected to test are based on this hypothesis. Nerve transmission Genes that are not related to the metabolites and play a role in the behavioral phenotype Were selected based on previous studies showing Additional criteria for selection are: A useful polymorphism associated with the candidate gene was to be available.   Second, twin studies have found that most multigene disorders (including ADHD and behavioral disorders) Shows that they are 50-90% genetic (Sherman et al., 1997; Slutske et al., 1997). Each genome accounts for only 1-2% of the variance, so simple calculations should at least Even showed that 20-40 genes should be included. The number depends on the given individual There may be less. Third, to avoid circular inference, Genotyping is independent of subjects studied by the present inventors or others. It was important to show that the group had efficacy in the group that responded. The present inventors Genes tested are listed in Table 65. The “proven” column shows the score used Indications indicate genes established in an independent group of subjects. Fourth, each remains The genes were scored with a value of 0, 1 or 2. For example, the double allele polymorphism If included and independent studies showed dominance for one allele, Scoring was 11 or 12 = 2 and 22 = 0. Independent studies are genotyped , At the same time showed dominance, the scoring was 11 = 2, 12 = 1, and 22 = It was 0. Similar three scoring techniques were used for repeated polymorphisms. This is each genetic Facilitates testing of additive effects in offspring, and that each gene is on a similar scale of 0-2 And allowed to be scored. Fifth, multigene disorders are common. Therefore, the fact that many genes are involved is due to the genetic alterations involved, Indicates that it should be very common in itself. From this, the present inventor Have polymorphisms and residuals to maximize the proportion of subjects scored 1 or 2. We explored the use of gene-type groupings. The results are shown in Table 65 It is shown at the bottom of the system% 1.2. In most cases, the sum of the 1 + 2 ratios is 25 par Note that it is larger than cents, and often larger than 50 percent thing.   Sixth, if the genetic variants involved in the polygenic disorder are common, they Must be fundamentally different from a genetic variant that causes a single genetic disorder No. That is, the genetically modified variants show only moderate changes in gene expression Must arise. Because, when a large change is caused in gene expression, If they cause a single genetic disorder (Comings, 1998b). This Based on these observations, the inventors have determined that the variable length of Z-DNA Therefore, the common dinucleotide repeat polymorphism itself is a major feature of polygenic heritable traits. (Comings, 1998b). These repetitions are many, Conflict Genes are common, and the formed Z-DNA has a modest effect on gene expression Effect. Significant phenotypic effects are associated with many different functionally related genes. It may only be produced by conferring the effect of a variant together. main research The potential importance of this for Was particularly interested in using Ndem repeat polymorphisms, and Any single base pair polymorphism is associated with one or more of the short tandem repeats associated with this gene. Seemed to be in linkage disequilibrium with the allele. For the latter reason We conclude that any single nucleotide polymorphism indicates that this polymorphism is an exon or Or provide valuable information about MAA technology, even when it is not associated with a promoter. It was assumed that it could be offered. Seventh, shadowing certain neurotransmitters or functional groups To test the additive effects of two or more genes that affect The variability of the so called dummy is simply added to the score for each individual gene. And set based on. Different sets of genes within a given functional group for the percentage of variance By testing the effect of the combination, you can add additional effects on the quantitative score. Identification of a subset of the genes involved. Then, this set of genes Transpolygenicity tested for additional effects of genes across different functional groups using A childhood score (TPG) was formed. As the PG or TPG score increases, the individual The number of phenotypically related genetic variants that are present increases.   Eighth, as in previous studies (Comings et al. 1996b; Comings et al., 1998a; Coming et al., 1 998b) Additional gene scores were investigated using linear regression analysis. This is a trial The gene being tested contributed to the trait^TwoOr the variance ratio can be calculated and the effect F to test the magnitude of p and p for significance of the effect were provided. Remains The fact that genes are responsible for the variance of the trait of about 1% indicates that the effect is almost It does not mean that there is no. Depending on the number of factors, this is the phenotype It can provide up to 10% of the predictability (r) of the effect (Rosenthal and Rubin, 1982; Ozer, 198 Five). Ninth, since the various action scores have different size ranges, the action score A, not cumulative^TwoUse values to determine the effect of 29 genes across different phenotypes Provided exact comparison.   Tenth, we have developed a DSM-IV based Attention Deficit Hyperactivity (ADHD) score (Diagnos tic and Statistical Manual of the American Psychiatric Assn.IV, 1994) Was initially selected to investigate. To emphasize the dichotomous diagnosis Rather, we set the ADHD score in individuals with different sets of genotypes. Use an approach that takes advantage of the full range of scores by comparing the means of Have been. Eleventh, regression analysis: two latents for using univariate and multivariate analysis There was a local approach. For univariate analysis, add a score for each gene To generate a single score and determine the correlation between this score and QTV. This was an extension of the 0,1,2,3 scoring approach. Advantages of this approach Increases the r-value only if one or more genes have an additive effect on QTV Was added. When a gene having a subtractive effect is added, r decreases Was. This is the final r and r^TwoIt was conservative for value determination. But, All gene scores are combined with a single variability, so the number of genes is Nevertheless, the degree of freedom was always one. It is non-conservative with respect to p-value .   For the second approach, the gene score for each individual is calculated using a multivariate regression equation. And correlated with QTV. The degrees of freedom increase as each gene is added This was conservative for the p-value. However, additive and subtractive inheritance Since both offspring contributed to r, this approach is Whether r is additive or subtractive,^TwoAbout the value And was non-conservative.   We chose the univariate approach for two reasons. First, this Is more conservative. Because both r and p values are genetic factors that do not contribute to QTV. This is because when a child is added, the number decreases. Second, the gene is Losing ability, as represented by a single degree of freedom, regardless of the number of children And has the potential to test the effects of hundreds of genes simultaneously.   Twelfth, examine the hypothesis that most disorders coexisting with ADHD share genes In order to achieve this, we also have rebellious behavioral disorders (ODD), behavioral disorders (CD), Of 29 genes for quantitative scores for, learning disability (LD), and other QTV The additional effect of the same set was investigated. For subjects over the age of 14, We have also found that alcohol abuse / dependence, drug abuse / dependency, and smoking of QTV was investigated. Thirteenth, the investigation of these comorbidities also suggests that we In addition to genes, different co-morbidities can affect several genes and certain phenotypes Made it possible to test the hypothesis of using unique gene combinations (C omings et al., 1996b; Comings et al., 1996a). Fourteenth, the gene of the individual and the predetermined phenotype Significance level of p <05 for the association between this gene had an additional effect In order to find out whether or not it affects whether^TwoAnd p-value Regarding whether it has an additive or subtractive effect on the current score, 145 Genotype association of the gene^TwoThe relationship between and p-value was investigated. Finally, all After the first pathway using candidate genes identified genes with additional effects, Additional genes are progressively added to the new TPG score and correlated with the QTV in question. It is. This was obtained using only those genes identified as contributing to the QTV in question. Total r^TwoForecasts were provided. Benefits of additional scores. The use of additional genetic scores is Are also unique aspects (additive effects of different genes, subtractive effects of different genes, heterogeneous effects) Cis and epistasis roles, and many different genes While contributing to the same phenotype in an individual or population of (The fact that only some can exist). Most importantly, this app Roaches can compensate for the presence of different sets of genes in different individuals. Follow Therefore, in many cases, one related study is repeated in several subsequent studies. It is not repeated in every subsequent study. This means that only a few genes And one set of genes involved in a group of subjects But due to the fact that another set is involved in a different group of subjects I do. It does not mean that one or the other result is incorrect, etc. A useful conclusion is that different sets of genes have the same phenotype in different groups of individuals. Can be generated. Additional scores are for the entire set of genes involved. Because it measures body effects, the MAA technique allows for much more There is reproducibility. To give a specific example, (TaqI A1 allele) (Comings et al., 1996b; B lum et al., 1998), DRD4 (7 repeats of 48 bp) (Lahost et al., 1995), DBH (TaqI B1 allele) (Genes) (Comings et al., 1996b), and DAT1 (10 repeat alleles) (Comings et al., 1996b) Cook et al., 1995; Gill et al., 1997; Waldmaqn et al., 1996) all variants of ADHD Although related in etiology, each has significant effects in a group of subjects. But may not in other groups. But the physiological effects When similar for each gene (modification in dopamine metabolism), for all four Additional assessment of HR is consistent in all groups of ADHD subjects versus controls And can prove to be significantly higher. This is etiologically significant in ADHD Shows an overall gene deficiency in dopamine metabolism instead of any single gene of interest You. This same rationale holds for additional genes across different neurotransmitter groups. That's true. The final strength of the additional score depends on the combination of different genes By use, the largest informative set is the best for the identification of a given phenotype. It can be optimized. Unlike the subtle effects of individual genes, Optimized sets can provide excellent predictive and diagnostic values. hypothesis. The first hypothesis is that a polygenic disorder has an additional synonymous gene. MAA techniques, rather than testing one gene at a time, It offers much greater ability in gene identification and has additional effects By including only these genes,^TwoAnd maximize the p-value. To test this For the purpose of the present inventors, we examined 274 individuals with Tourette syndrome and 62 control individuals. Of 29 genes in 336 Caucasian individuals consisting of The effect was investigated. The second hypothesis is that two independent samples are When examined, we find that different samples utilize different sets of genes. Many but not all additional genes in one sample All that is additive in the test sample and subtractive in one sample Not many genes are subtractive in retest samples and some genes Is additive in one sample and subtractive in the retest sample; And for both samples, the additive effect of the synonymous gene is We hypothesized that the effect was significantly higher. We also note that r^TwoChanges in N Was expected to increase as they became smaller. To test this, 336 Subjects were equal in number of TS and control subjects in each group and They were randomly divided into two independent sets of 168 subjects with equal numbers of women. ADHD Score The correlation between PG and TPG score for (a) was investigated for each set. Third The hypothesis is that when different phenotypes are tested, we Comorbidity disorders share some ADHD genes, while some genes and It was hypothesized that combinations of genes and genes were unique to comorbidities. this To test, we used different QTV-rebellious behavioral disorders, behavioral disorders, ticks. Additive and subtractive effects of all 29 genes on learning disabilities and other disorders investigated. Study Subjects The study group consisted of 336 unrelated, non-Hispanic white subjects. It became. Of these, 274 were diagnosed with Tourette's syndrome (TS) and 62 The name was the control. TS subjects were tested at the City of Hope Medical Center Subjects from Tourette syndrome clinic. Everyone, DSM-IV standard for TS And all were personally interviewed by the inventor. These are the earlier Mainly the same as the subjects tested in the study (Comings, 1995a; Comings, 1990) If the DNA samples of some of the subjects used in previous studies were depleted, That new TS proband has been added. We have previously tested our TS test. Mild body (stage 1, chronic tics too mild to treat), moderate (stage 2, treatment Serious enough to need), and serious (stage 3, some aspects of their life). And has very significant impact) (Comings and Comings, 1987b). TS subject Between 30% were in stage 3, 62% were in stage 2, and 8% were in stage 1. Was. TS and ADHD are similar disorders, with the majority of TS subjects going to the hospital ADHD coexists (Comings and Comings, 1987b; Comings and Comings, 1984) ). 54% of the TS subjects met the DSM-IV criteria for ADHD. control And the presence of subjects with ADHD and TS subjects without ADHD Groups as progressive variability of the association between alleles of different genes and ADHD Make it particularly well-suited for research. The average age of TS subjects is 18.0 years (S.D. 13.2). Most were older children and adolescents, but 29% were 21 or older. Above there were. The mean age of the controls was 46.3 years (S.D. 15.38). TS subject And controls have been described elsewhere (Comings et al., 1996b; Co mings, 1995a; Comings, 1994b; Comings, 1994a; Comings, 1995b).   Each control and TS proband will have an interview schedule (Rob ins et al., 1981), DSM-III-R (Diagnostic and Statistical Manual of Mental Disor) ders, 1987) and DSM-IV (Diagnostic and Statistical Manual of the American  Psychiatric Assn. (IV, 1994). I was demanded to. The question is that during childhood and adolescence, no DSM-IV ADHD symptoms were Whether it was hard or rare (score = 0), occasional (score = 1), Was always asked (score = 2). Rebellious behavior disorder ( For measures of ODD) and behavioral disorders (CD), the DSM-IV criteria for these disorders Based on the sum of the numbers. Test subjects to assess the presence of problems with learning disabilities I asked my body three questions. 1.Educational disabilities (EH), learning disabilities (learning hand icapped) (LH) or special class for learning disorder (LD) 2. Have you ever been enrolled in a resource class Have you ever been told that you have a learning disability? Each question is , No = 0, or Yes = 1, evaluated and added to form an LD score. Caliph In one of the special classes listed above, one or more educations are required Full assessment by psychologists and students are more than two years behind their peers Need to be evaluated. Alcohol score (Comings, 1994b) Abuse / dependency based on sum of DSM-IV symptoms. Tic score is a range of motility Based on the sum of the presence of tics and vocal tics (Comings, 1995a). Behavioral score The specific questions used for the question are described in more detail elsewhere (Comings et al., 199 6b; Comings et al., 1998a; Comings, 1995a; Comings, 1990; Comings, 1994a; Robins et al., 1981; Comings, 1995c; Comings, 1994c). This survey, We reviewed with each subject to ensure its accuracy. Ann for symptom evaluation The accuracy, availability, and sensitivity of the Kate-based approach are Compared to the treatment of the tool with the same configuration as the interview, other researchers (Gad ow and Sprafkin, 1994; demonstrated by Grayson and Carlson, 1991) Have been.   Even with a randomly scored set of alleles, only the additional genes When used, each gene was analyzed to investigate its potential for significant effects. , The algorithm that resulted in the same final allele frequency as reported in Table 65 Scores of 0 and 2 were assigned based on random number truncation in.   We have calculated the exact p-value for the large F-value obtained in the linear regression analysis. To provide the dstatt10.exe program (http://odin.mdacc.tmc.edu/anonftp /) Was used. Linear χ^TwoAnalysis can be used to determine the level of genes in subjects with ADHD Were tested for significant differences in the number of genes in subjects without ADHD Was. SPSS statistical software obtained from SPSS, Inc. (Chicago, IL) was used. result. Table 65 includes 29 gene names, polymorphism types, and techniques for genotyping Reference to polymorphism, how genotype was scored, scored as 1 or 2 Percentage of subjects who were exposed to genotypes in an independent set of subjects List whether there was a law check and, where available, a reference to this . To test Hypothesis # 1, a progressive PG and TPG gene scan for ADHD variability R, r of the core^Two, F, and p values were calculated by linear regression analysis (Table 66). result In demonstrating, we consider neurotransmitters or the functions they affect. The genes were divided into the following groups. Dopamine gene. All five dopamine receptor genes and dopamine transport genes The offspring (DAT1) were investigated. Of these, DRD2 (Comings et al., 1996b; Comings et al., 1991) , DRD4 (Lahoste et al., 1996; Swanson et al., 1998) and DAT1 (Comings et al., 1996b; Gill Et al., 1997) have already been linked to ADHD. DRD1, DRD2, DRD5, And DAT1 genes have ADHD scores (r in the range of 0.0022 to 0.0088).^TwoValue) Had the greatest effect. Each p-value ranged from 0.388 to 0.093 . Although the DRD4 gene plays no role in ADHD in this study, To match, we have determined that bialleles can also be important. Despite their own studies (Comings et al., 1997a), this gene was Scoring emphasized the longer 6-8 repeat alleles.   According to the PG score, the DRD1 and DRD2 genes have their respective r^TwoSum of values (0. 041 + 0.0084 = 0.0125) is the same as the PG score (0.0125) observed for D1 + D2. As such, they are additive in their effect. We have added these to It is called a gene. In contrast, the DRD3 gene score was added to the D1 + D2 PG score If the r obtained^TwoIs less than the score for the DRD1 + DRD2 gene (0.0092). Thus, with respect to the ADHD phenotype, we referred to these as DRD3 subtractive genes. did. r^TwoContinue to decrease with the addition of the DRD4 gene (0.0071), It was also considered a subtractive gene. r^TwoThe value also affects the addition of the DRD5 and DAT1 genes. These are therefore considered as additional genes as they increase. Only additional genes Is included in the PG score,^TwoValues are for both additive and subtractive genes. It was 0.0208 compared to 0.0138 when it was included in the PG score.   Based on these results, we have found that by adding the gene, r^TwoIncreases and F Additional role of gene in phenotype when p increases and p decreases But if these values are reversed, the subtractive effect on the phenotype Has been formulated. In the remainder of these studies, we have , Not a variable p-value, but a basis for the involvement of genes in PG or TPG scores As a reference, this formula was chosen. Therefore, the present inventors have evaluated the TPD score. As a set of additional dopaminergic genes (D), DRD1, DRD2, DRD5, and D AT1 was selected. Together with these, the four dopaminergic genes contribute to the ADHD score. , 2. It is responsible for 08% variance (p † = † 0.0081). Serotonin gene. R for the six serotonin genes^TwoValues are for serotonin Transmission (HTT) ranged from 0.0106 to 0.0002 for the HTR2C gene. HTR1A If the gene is added to the HTT gene, r^TwoValue increased from 0.0106 to 0.0143 . The HTR1Dβ gene was added and increased after the addition of the HTR2A gene. And increased with the TDO2 gene, r^TwoThe value dropped. This means that HTT, HTRIA, HTR2A, and TDO2 genes have additional serotoninergic effects. It suggested that it was the optimal set of genes. R for these genes^Twovalue Was 0.0161. However, the r of the HTR2A gene^TwoThe value (0.0016) is the lowest of the four Thus, we also have r r for HTT, HTR1A, and TDO2.^TwoIt was determined . Since this is higher (0.0167), the HTR2A gene is associated with a serotonergic gene. Removed from the additional set. Excluding this gene, the next lower r^TwoAlso have a value Is an additional r^TwoDid not increase the value. Together with these four genes , 1.67% variance in ADHD score (p † = 0.018). Additional dopamine crop If utility and serotonergic genes were added, they would be 3.7% Caused a variance in the ADHD score (p の = 0.0004). Norepinephrine gene. R for the four norepinephrine acting genes^Two Values ranged from 0.0066 to 0.00122. In this case, all four genes are all r^TwoIt had a progressive additive effect on the value. Collectively, these are 4.22% ADH It is responsible for the variance of the D-score (p † = 0.00015), which is due to the norepinephrine gene Is the dopamine or serotonin gene, or the combined dopamine or It was shown to play a greater role in ADHD than the serotonin gene. fact The two noradrenergic α2 receptor genes themselves account for the ADHD score. It is almost the same as scatter (3.44%). Because dopamine or This is because the rotonin gene was combined. These adrenaline in ADHD Further details of the role of the acting gene are given elsewhere (Comings et al., 1998a). Of dopaminergic and serotonergic and noradrenergic genes When the effects (DSN TPG scores) are combined, they are divided by an ADHD score of 7.41%. Scattered (p † = 0.0000040). Catecholamine degradation gene. AD for two catecholamine degradation genes HD Score r^TwoValues range from 0.0244 for the MAOA gene to 0.0098 for the COMT gene. Was in the range. When added (C), they are the source of the variance of the ADHD score of 3.33%. (P † = 0.00077). When added to the DSN score, they are 10.05% Was responsible for the variance in the ADHD score of (p = 2.8 × 10^-8). GABA receptor gene. ADHD scores for two GABA receptor genes^Two Values range from 0.0082 for GABR3 gene to 0.0066 for GABRB3 gene Met. R for two combinations^TwoThe value was 0.0143 (p † = 0.028) . When DSN and C scores are combined, they have a variance of 10.87% ADHD score. Was the cause (p † = 5.9 × 10^-9). Other neurotransmitter genes. R for four additional neurotransmitter genes^Twovalue 0.0017 for cannabinoid receptor gene CNR1, nicotinic choline production 0.0143 for α4 gene CHNRA4 and NMDA receptor gene NMDAR1 Was 0.0058 and 0.0011 for the proenkephalin gene PENK. Each is ahead Variance in the ADHD score was 11.09%, 11.78%, 12% It gradually increased to .26% and 12.34%. Neurotransmitter-related genes For the whole unit (NT), p † = 3.4 × 10^-TenMet. Androgen receptor gene. All behaviors we tested were male We have also investigated the AR gene as it is more common. ADHD, OD Details of the role of this gene in D and CD are given elsewhere (Comings et al., 1998. b). ADHD score for AR gene^TwoThe value was 0.0111. On the gene ahead When added, these are responsible for the variance of the ADHD score of 13.27% (p † = 5.5 × 10^-11). Immune gene. Immune factors in ADHD (Warren et al., 1995) and TS (Swedo et al., 1998) Due to recent interest in a potential role, we have identified two immune genes, Interferon-γ and CD8A genes were investigated. Both are subtractive genes Proven to be, and was not included in the additional set. Other genes. Two other genes, presenilin-1 (PS1) and corticotrophy The release factor gene (CRF) was tested. R for both^TwoValues are similar but (0.0 051 and 0.0050), only the CRF gene was additive. Group all additional genes When combined, they were responsible for the 13.62% variance in the ADHD score (p = 2. 8 × 10^-11). ADHD Score FIG. 4 shows the effect of increasing the number of variant additional genes in the ADHD score. The result is shown. This is from 1.0 for the score of the 4 or 5 variant gene to 1 There was a tendency for a progressive increase in the score of the 5 variant genes to 25.0. A Gradually increasing linear χ in DHD score^TwoThe p-value for the test is <10^-8So Was.   FIG. 5 shows r for all progressive additions of the 29 genes tested.^TwoIndicates a value. Heredity The slope of the curve to the immediate left of the offspring label is the relative of this gene in the ADHD score. An index of contribution was provided. If the slope increases, the gene contributes to the ADHD score Was. It contributes more as the angle of inclination increases. If the slope becomes smaller, Genes are subtractive and are always scored relative to other genes. Larger table for genotypes where the first gene scores 1 or 2 Despite the fact that it showed a prototype effect, almost nowhere in the ADHD score Played no role at all. This allows DRD1, DRD2, DRD5, and DAT1 The dopamine gene contributed to the ADHD score, while the DRD3 and DRD4 genes It was determined that the child did not contribute. HTT, H among serotonergic genes TR1A and TDO2 genes contributed to the ADHD score, while HTR2A, HDO2 The gene for TR2C did not contribute. These four noradrenergic genes are More likely to be on the ADHD score than on any other neurotransmitter group Gave. If all 29 additional and subtractive genes are involved, the final r^Twovalue Is 0.113, p † = 2.7 × 10^-9Met.   We will assume that if the same set of genes is randomly assigned to alleles, , Only genes that positively correlate with the ADHD score can be used and the resulting r^TwoYes Investigated the possibility of being willing. The result is shown in the lower part of FIG. r^TwoValue progress Additional effects are indicated by white squares, and additional effects using only positive correlation Indicated by squares containing X. Final using both additive and subtractive genes r^TwoThe value was 0.0001. Final r using only additional random genes^Twovalue Was 0.0004. None were significant. Further, the cumulative r^TwoThe value is The height of the random PENK gene was about 0.008. When an additional gene (CD8A) was added, it fell back to 0.0004.   To test the potentially confusing role of gender, we examined male and female And women were investigated separately. Both groups had a reduced ability of a small number of subjects in each group Mainly reduced by r^TwoValues showed a significant increase.   Therefore, the test of hypothesis # 1 shows that the additional effect of 29 genes is greater than any single gene Significantly larger r^TwoAnd p values. And r^TwoAnd p-value It was greatest when only additional genes were used. Figure 6 shows the results of the hypothesis # 2 test. Shown in This indicates that the observed results were consistent with the hypothesized results. 14 Genes are additive in both sets and 2 is reduced in both sets. Arithmetic, 13 was different in both sets. Generally, all sets And the most additional genes (e.g., DRD5, DAT1, HTT, HTR1A) Narinergic genes (DBH, ADRA2C, ADRA2C, NT), MAOA, COMT, and AR genes Was an additional gene in both sets. And in all sets, The most subtractive genes DRD3, DRD4 were subtractive in both sets. Two The most significantly different genes in the set were CNR1, CNRA4, NMDAR1, and PENK Was the gene. For example, the NMDAR1 gene is extremely additive in group 2. However, in group 1 it was subtractive. However, in both sets, N is <† 5.0 × 10 despite being smaller^-FourWith final p-values for both^Two There was a progressive increase in If only additional genes were involved, both Is p <10^-6Was significant. Of these genes, which are additive for both groups Miga When used in all sets, r^Two= 0.108, F = 40.82, p † = 5.6 × 10^-9so there were. These genes, which are additive in both or only one set, When used in a set, r^Two= 0.11, F = 43.71, p = 1.5 × 10^-9Met. This These results show difficulty in frequency in replication when a single gene is tested More useful for. In contrast, the MAA technology, under a range of conditions, Cause the result. 4, 5, and 6 show that the coexistence state is common in ADHD. Shows test for hypothesis # 3 that shares genes and uses some unique genes You. ODD and CD. R for ODD and CD scores^TwoThe effect of 29 genes on the values Tested. When both additional and subtractive genes were involved, the ODD score Maximum r^TwoIs 0.775, p † = 3.1 × 10^-6Met. And CD score Was 0.0255, p = 0.0059. Also, by inspection, ODD and CD These genes that contribute to the score can be easily identified. Additional genes Maximum only for ODD score if only used^TwoIs 0.10 and p † = 3. 2 × 10^-8Met. And the CD score is 0.075, p † = 3.7 × 10^-6 Met. The most important genes for ODD are DRD1, DRD2, DRD3, DAT1, HTT, HT R1A, HTR2A, HTR2C, DBH, ADRA2A, ADRA2C, MAOA, GABRA3, GABRB3, CNR1, CHRN A4, NMDAR1, PENK, AR, and CD8A. The most important genes for CD are DRD1, DRD2, HTT, HTR1A, HTR2A, HTR2C, DBH, ADR2C, CHRNA4, AR, and CD8A It became. Thus, 20 out of 29 genes play a role in ADHD and OD 20 genes play a role in D and 10 genes play a role in CD Was. The ODD gene is similar or different from the ADHD gene, but all of the CD gene Was the same for ADHD scores. LD and ticks. R for LD and tic score^TwoEffect of 29 genes on values The fruits were investigated. If both additional and subtractive genes are involved, The maximum r^TwoIs 0.011, p = 0.054, and the tick score is Was 0.014 and p † = 0.029. If only additional genes are involved, The maximum r^TwoIs 0.043, p = 0.0005, and the tick score is 0. 061, p = 0.00005. Observation also shows that genetics involved in the tic score Children are DRD1, DRD5, HTR1A, HTRIDβ, HTR2C, TD02, DBH, ADR2C, COMT, GABRA3, C NR1 and CHRNA4 are shown. The gene involved in LD score is DRD 1, HTR2C, TD02, DBH, ADRA2A, ADR2C, MAOA, CNR1, and CNRA4 Is shown. Thus, 12 genes are involved in tics and 9 genes are involved in learning disabilities. Was. Alcohol / Drug Abuse / Dependency and Smoking Alco of 164 subjects over the age of 14 The results of testing 29 genes for abuse / dependency scores were investigated. N is smaller If so, r^TwoThere is a wide variation in the values. Therefore, only adults are tested If so, the additional gene is easily distinguished from the subtractive gene. Alcohol abuse For / dependent QTV, the final r using both sets of genes^TwoIs 0.049, p † = 0.0044. However, if only additional genes are used, r^TwoValue is 0.14 , P † = 7.5 × 10^-6Met. As discussed below, these genes or Many of the neurotransmitter systems were previously implicated in playing a role in alcoholism. I have.   Drug abuse / dependence QTV (excluding smoking) results for alcohol abuse / dependence Similar to the result. However, substance abuse is more prevalent than alcohol abuse / dependency There is no^TwoThe magnitude of the line for the value was smaller. The big difference is H TR1Dβ and HTR2A, ADRA2C genes are subtractive in drug abuse / dependence, HTR2C and NT are additive in alcohol abuse / dependency Is additive in drug abuse but subtractive in alcohol abuse; And INFG is subtractive in alcohol abuse, but in drug abuse It was neutral. Smoking is more common and these results are also Was done. Here QTV has been smoking for more than a month = 1, Never scored = 0. In the subject of this experiment, the DRD2 gene Is r^TwoPlayed an important role in itself causing the value to be 0.055. other Additional genes were NMDAR1, PENK, AR, and INFG. Final r^Two= 0.1 0, p = 0.00038. Other QTV We also have some other beliefs about behaviors that commonly coexist with ADHD. QTV was inspected. Whole r^TwoValues, p-values, and major additional genes are as follows: Had been: manic --- r^Two† = 0.0721, p † = 5.8 × 10^-6, DRD1, DRD2, DRD3, D AT1, HTR1Dβ, HTR2C, TDO2, ADRA2C, GABRB3, CNR1, CHRNA4; Schizophrenia^Two= 0 .058, p = 8.3 × 10^-Five, DRD2, DRD3, HTR1Dβ, HTR1A, HTR2A, HTR2C, DBH, CNR1 , CHRNA4; OCD --- 0.46, 1.0 × 10^-Four, DRD1, DRD2, HTR1Dβ, GABRB3, CNR1, NMDA R1 ： General anxiety --- r^Two= 0.032, p = 0.001, DRD1, DAT1, HTR1Dβ, CHRNA4, PEN K; and serious depression --- r^Two= 0.0271, p = 0.0025, DRD1, DAT1, HTT, HTR1Dβ , TDO2, CNR1, CHRNA4, NMDAR1. Number of genes involved. In subjects with and without a specific dichotomous phenotype In order to investigate the relative distribution of the number of variant genes, we studied ADHD. Have no DSM-IV criteria for ADHD for subjects who meet all DSM-IV criteria The number of additional variant genes in the subject was plotted (FIG. 7). Average number of variants Is about 10 in subjects without ADHD symptoms and in subjects diagnosed with ADHD It was about 12. In subjects without ADHD symptoms, the distribution range is 3-1 0, but in subjects diagnosed with ADHD, the distribution ranges from 7 to 18. there were. Additional effects on p-values From this study, we found five quantitative scores (ADHD , ODD, CD, LD, and tic)).^TwoAnd And p-value results for subjects who are subtractive for the phenotype in question , Additional subjects were identified. This is when the genes are examined one at a time , P-value arbitrarily set at <0.05 indicates that the gene is additive and contributes to the phenotype. Or whether the gene is subtractive and does not contribute to the phenotype , Indicating little relevance. Most additional artifacts, when examined individually Genes have p-values greater than 0.05, and can often have p-values between 0.10 and 0.40. A p-value greater than 0.45 was generally identified as a subtractive gene, while the p-value was 0. If in the range of 12 to 0.45, some are additive and some are not. won. Discussion Concerns about the difficulty of identifying genes involved in polygenic disorders I have mentioned it often. In this study, we found that a single genetic disorder Key features, additional effects of many different genes, additional effects of multiple candidate genes Attempts have been made to reflect on the benefits of investigating. Additional related studies We use this as a multiple additional related It was called. When using chaining techniques to investigate complex obstacles, very high Suggests that false positives must be avoided using the significance of the level of density (Lander and Krugyak, 1996). For this recommendation, see Table 66 and Figure 5 In FIG. 6 and FIG. 6, we showed the full p-value instead of the truncated p-value. . This indicates that using MAA technology, only 29 genes and 344 subjects, 10^-11For up to Shows that the p-value is easily achieved.   Because this is a new technique, carefully examine the statistical approach used That makes sense. Clearly fair to some potential criticism Is big. First, if the study was performed on a single group of subjects only, Gene score if the effect is set to be greater than the effect for a given phenotype If the injury is set to maximize the effect on the given phenotype, simply By adding their gene scores together,^TwoAs the value increases, Result. To this end, the present inventors have described them or their references. Genes in another group of subjects studied by any of the other researchers The scoring was checked carefully. As shown in Table 65, all genes meet this criterion. Filled. For some genes, there is only one feasible scoring Exist. For example, for a gene having two allelic variants, one allele If the offspring frequency is low, then there are few 11 genotypes. That is, 22 = 0 and There is no alternative to scoring, 11 or 12 = 2.   A second potential criticism is that sufficient genes have been investigated and only additional genes have been used. If used, it is possible to obtain significant results on a random basis That is. In order to investigate this possibility, we have determined for each individual Each “dummy gene” is designed to match the frequency found in the observed results. A second set of scores randomly assigned a score having a defined frequency It was set. The effect of progressively adding both positive and negative results is shown in FIG. (White square). Depending on the end of the 29th gene, negative vs. positive results Offset, final r^TwoWas 0.001. More importantly, give a positive correlation If only random genes were used, the exchangeable r^TwoValues are for PENK gene Increased to a maximum of 0.006. However, the final two positive random genes After being added, r^TwoThe value drops to 0.004 (p> 0.25). This subtractive effect is probably Even if the effects of CD8A and CRF random scores are positive, r^TwoValue is 0.00 It is in the range of 00-0.0003 and is due to the fact that it produces a subtractive effect. Positive r Multiple interactions of the same process, using only interactions with Although significant results could be produced, the important point is that other studies related to phenotypic effects When using independently identified candidate genes, the final p-value is Dramatically higher than the gene (10^-Five~Ten^-11).   A third potential criticism is that the results are clearer than expected from random scoring. The use of univariate regression, if any, and that only additional genes are involved. Means significantly increasing the obtained p-value. This very reasonable criticism There are two approaches to format. The first is the routine means of all genetic research Is the duplication and investigation of a multi-dependent set. We have developed MAA technology The rational standard for is that in studies where the additional set has a reasonable N Suggest that all genes indicated to be included should be included. For example In our own test retest studies, a selected set of additional genes May include additional genes that are additional in any set. these Since some are subtractive in some studies, this^TwoAnd p-value To avoid artificial rise. If this is done, the final r^TwoIs , More subtractive, 0.11, highly significant, p <2.0 × 10^-9It is. Reason for subtractive effect The appropriate subtractive effect is that the variance percentage depends on the gene in question. This can be attributed to the fact that relatively small things are responsible. For example, gene A 11 If the genotype had a very small effect on the ADHD score, another gene would be A1 It may be the cause of non-A11 subjects with an ADHD score higher than one subject. Non-A11 test The body can have more significant symptoms, resulting in a subtractive effect of the gene. I will. A second reason for the subtractive effect occurs when many different phenotypes are tested. obtain. For example, 11 genotypes of a gene can be significantly associated with ADHD, while 22 Types can be associated with different phenotypes, such as depression. As a result, a score of 11 This may have an additional effect on the ADHD score, such as where genotype = 2. But has a subtractive effect on depression scores. Associations for genetic studies of complex disorders. We believe that these studies are intense. Not only for theological genetics, but also for the genetics of complex polygenic disorders in general Think of having many associations. 1. Ability to test multiple genes against a single gene. It provides some insight into the problems with reproducibility of related studies testing genes. This This is most likely due to the fact that synonyms Offspring are not important, and each gene contributes only a few percent variance. As a result, if genes are tested one at a time, one gene will be included in one study. But is not significant in another experiment. A constant source of frustration (Moldi n, 1997) or not the idea that none of the studies is accurate, Should be considered as predicted outcomes in the genetics of various disorders (Comings, 1998a ). Proportion of variance for results in 145 related studies using genes and behavioral traits We report here and the p-value (excluding alcohol abuse / dependence). This is because most of the additional genes are on a general basis for the significance of a single gene. If a certain p <0.05 is used, it indicates rejection. Why two research institutes , P <0.05 was difficult to match using a cutoff? Indicate the reason. R 0.008 to 0.025^TwoThe relevance that generates the value is from different Only 6 or 20% are considered positive if they are actually independent studies , The remaining 24 are considered negative “non-replicating”. However, with MAA technology, all functions Linkage can be used.   Because the single most different characteristic of polygenic traits is the involvement of synonymous genes We use this property to identify genes involved in complex disorders (Comings et al., 1996b; Comings et al., 1996) a; Comings, 1998a; Comings, 1998b). This study confirms this concept, and The ability in the transgenic trait is derived from an investigation of the additional effects of the synonymous gene Is shown. We also ask whether genes play a role in a given disorder. The appropriate criterion for determining is the subtractive effect on the associated quantitative score and Rather, it suggests whether it has additional effects. this is, Easily identified by presenting the results shown in Table 66, or FIGS. 5 and 6 Can be done. 2. Related research as the optimal approach to polygenic traits Whole genome screen using rodscore linkage using common methods Complex obstacles consisting of lingering, affected sib-vs. Technology, or haplotype relative risk technology The gene in is identified. This method has significant inherent logic, but replication is Are often difficult, and we believe that ADHD or Or many of the above genes that have been found to play a role in TS It has been “excluded” on the basis of research (Pakstis et al., 1991). Unrelated control And related studies using significantly affected probands have identified polygenic heritable traits. Has its own ability to detect small effects on features (Risch and Meri kaugas, 1996; Comings, 1998a), but they also suffer from non-replicating problems. Synonymous remains MAA techniques to investigate the additional effects of genes harness the power of related research and Avoid the problem of non-duplication. This is cumulative r^TwoHas an additional effect on With single gene at p <0.05 with less stringent parameters This is in order to replace the standard of will. This approach is also more practical . Identification of one unrelated proband and unrelated control (Researched using the same instrument) is much easier than identifying affected sib pairs is there. DNA efforts in identifying genes involved in many different disorders The link is set up solely from affected and unaffected sib pairs. Case confirmation Speed and the gene discovery capabilities of these banks are both single proband and A comparable number of unrelated controls screened using the same test equipment By including, it can increase dramatically. This efficacy is Sharing the same publicly available set of controls with different banks Can be maximized by CEPH (Centre d'etude du Polymorphisme Humain) (Dau (sset et al., 1990). The results are further enhanced by requiring publicity, and Their results can be matched.   This result provides additional reasons why association studies are more powerful than family-based linkage techniques. provide. This is when these two optimally disparate groups are used Show that the total number of variant genes is only moderately different (vs. 12 Average 10). This is a rods that actually or implicitly compares morbidity to unaffected Core, sib-pair, haplotype relative risk and TDT analysis (Spielman and Ewens, 19 There is not much difference when comparisons are made within families, as occurs in 96). At once If the problem is exacerbated by testing only one gene, too many The body is required to detect related genes even at border rod or p-values . By way of example, to date, the use of too many families and siblings has Most of the disability linkage studies did not identify any specific genes. This is the figure This is in contrast to the results in FIGS. 5 and 6. Here, the use of less than 350 subjects About 20 specific genes for ADHD and alcohol abuse / dependency Of the 15 specific genes were conditionally identified and the relative Generate data that allows estimation of importance. 3. Hidden ethnic group stage formation issues One concern is the potential problem of forming a hidden racial group stage. MAA technology Minimize concerns about the following reasons: Hidden racial group staging is a single legacy May play a role when testing genes, but the frequency of all genes changes in the same direction. It doesn't seem to be the case. As the number of genes tested increases The potential effect of forming a hidden racial group stage is reduced. 4. Issues of investigating many genes Another purpose is that if you find enough genes, some are only incidental. That is to say. This is particularly useful when the genes are tested all at once. It is. And the end point is a p-value of <0.05. However, additional multi-related technologies Independent of the p-value of the individual gene and in the background of other genes The gene has the phenotype r in an additive or subtractive manner^TwoWhether it contributes to I need it. By enhancing this property of polygenic disorders, this technology has Qualitatively and naturally adapts to the investigation of a large number of candidate genes. This allows the tic , LD, and alcohol abuse / dependency scores^TwoFluctuations in the value Can be This means that hundreds of genes have been added and the final r^TwoThe value continues to fluctuate Suggest that However, if this subset of genes is utilized, As the number of genes identified increases, so does the number of additional genes identified Typical^TwoThe value also rises. Thus, as each additional gene is tested, capacity is impaired. In contrast to the one-at-a-time losing approach, the ability of additional multiple related technologies It increases as more genes are tested. 5. Co-morbidity utilizes a related set of genes. Major phenotypes examined were rebellious behavioral disorders, behavioral disorders, and alcohol abuse / Dependence, substance abuse / dependence, smoking, OCD, mania, schizophrenia, and other representative R There are additional effects of many ADHD genes in related phenotypes such as DS behavior Was. 6. Comorbid disorders utilize different sets of genes. In addition to use, co-morbidities can have different phenotypes. Because they are different This is because a set of genes is used. Two observations are suggested later. First Finally, even when only additional genes are used, the final r^TwoValues are ODD, CD, LD, Ticks, and other scores, were lower for ADHD scores. Departure The authors note that the overall genetic contribution to each of these phenotypes If we assume that the contribution is similar to that of Is r to a comparable level^TwoMust be involved in raising value. This This suggests that, in addition to gene sharing, these comorbidities also use unique genes. Indicates that Second, accumulation using both additive and subtractive genes Typical^TwoThe slope of the straight line for the value indicates that the comorbidity disorder has a different set of genes or Fig. 7 shows the use of different genotypes For example, the MAOA gene has And additive, but subtractive for alcohol abuse / dependency scores. This indicates that the MAOA gene has a higher alcohol abuse / dependency score than does the ADHD score. About less important. 7.Different phenotypes may use different genotypes Use different sets of genes An alternative is that different phenotypes can use different genotypes. Also, MAOA Using the gene as an example is the reason that this is Instead, they can use different genotypes instead. Further examples As an indication, depression and aggression were often associated with low CNS serotonin levels ( Brown et al., 1982; Coccaro et al., 1989), while threatening behavior increases CNS serotonin. Or increased receptor sensitivity (Insel et al., 1985). Therefore, Certain genotypes were positively associated with depression / aggression but negatively associated with threatening behavior Not surprising, though. These observations make the gene scoring The question arises as to whether or not the current type should be individualized. We have individually Should be scored, which means that each such scoring is independent Guess what needs to be confirmed in the test subject. 8. Use of different polymorphisms In this study, we found one polymorphism per gene. Only the type was used. Use of other polymorphisms, and some polymorphisms to haplotypes The gender combination is potentially r^TwoThe value can be increased. Therefore, it is observed here Whole r^TwoThe values actually represent the true contribution of these genes for each phenotype. Can be significantly underestimated. 9. Comparable effects of different individual genes in different phenotypes The strongest of MAA technology One of the powerful aspects is the ability to identify the relative importance of different genes. this is This is possible because all genes are examined in the same group of subjects. Example is AR inheritance It is the child's role. Immediately after the AR gene for ADHD (Figure 5), ODD, and CD scores R on the left^TwoThe increase in the slope of the curve indicates the phase of this gene in all three states. Demonstrate opposite importance. In contrast, the AR gene is subtractive, with tic and LD scores Plays no role and is neutral about alcohol abuse / dependency scores. Was. 10. Comparable effects of different groups of genes in different phenotypes Another aspect of MAA technology Is an important role for genes that affect neurotransmitters specific to different phenotypes The ability to identify a percent. Thus, the set of four adrenergic genes is Played a significant role in the ADHD score. Collectively, they are 42% total based on child^TwoIt is the cause of the dispersion of the score. By comparison, serotonin Action genes accounted for only 9.5% of the total. This is the norepine Consistent with many studies that strongly link defects in furin metabolism (Halperin et al. Pliszka et al., 1996; Arnsten et al., 1996). By comparison, about disability The opposite trend is seen. Here, the serotonergic gene is based on the additional gene. And all r^TwoAdrenergic genes were responsible for 30% of the variance in The cause was only 13%. This is central serotonin metabolism in antisocial behavior (Brown, 1982; Lindberg et al., 1985; Coc). caro et al., 1997). 11. Relevance for the publication of multi-step and single-gene studies for related studies   The results of MAA's technology indicate that relevant research should be conducted in multiple stages. And suggest. In the first stage, which polymorphisms can be useful and Preliminary studies one gene at a time to determine if they should be encoded as in The ultimate need exists. However, we have found that important The insight is how the genotype of a given gene polymorphism should be scored. Suggest that. Depending on the sample size, even with a p-value> 0.05 , This information can be valuable. > 0.005 r^TwoOr most of which gave r of> 0.07 Single association study is additive, and when N is appropriate, this is not a p <0.05 Can be a standard for disclosure.   The second step is the use of MAA technology that utilizes all reasonable candidate genes. These results represent the straight lines of the additive and subtractive genes in FIG. 2 shows non-selective inclusion of genes. The third step is to use only additional genes Development of a “new model” for a given phenotype based on This is shown in FIG. Are represented by a straight line for additional genes. The final stage is a new additional Genes are identified, progressively tested, and based on an accumulating set of additional genes. And an independent replication study that retests the resulting “new model”. 12. Genes for alcoholism, substance abuse, and smoking At least some forms of alcoholism, substance abuse, and smoking Identification of the specific genes involved and involved in one gene at a time approach It clearly shows that it is not significantly effective. In fact, DRD2 remains Reported association between the genetic TaqAI allele and alcoholism (Blum et al., 1990 For b), a combination of replicating and non-replicating (Noble, 1993; Blum et al., 1995b) It was one of the contributions to skepticism about the ability of continuous research. Alcohol abuse / dependency The results of using MAA technology on the core are related to the molecular genetics of alcoholism Provides insight into many issues. First, the r immediately to the left of the DRD2 gene^TwoSteeper curve Using the TaqA1 / A2 polymorphism, the DRD2 gene is Show your role in the score. However, this is^Two10% of the score And only all^TwoWith a score of only 0.14, this gene , Was responsible for only 1.4% of the total variance in alcohol abuse / dependency scores. this is, A fairly representative additional gene, replication using a one gene at a time approach This is a major reason that is very difficult. Second, dopaminergic, seroto D All genes in the active and GAGB active set are important for alcohol score Played a role. Third, the performance of MAA technology is very significant.^TwoValue (p † = 7 .5 × 10^-6). Compared to our findings, for comparable N This means that any conclusions previously reported using the one-gene-at-a-time approach Far more than a fruit. Fourth, the focus of this research is ADHD, not alcoholism But a very large number of genes shared by ADHD and alcoholism (DRD1 , DRD2, DAT1, HTT, HTR1A, DBA, ADRA2C, GABRB3, CNR1, NMDA, and CRF) Consistent with ADHD in alcoholism and high frequency of alcoholism in ADHD (Loney et al., 1981; Cantwell, 1972; Alterman et al., 1983; Tarter, 1988; Biederma n et al., 1995).   The results for smoking showed a strong effect of the DRD2 gene. But these Since the subject had Tourette's Syndrome, it was itself associated with the DRD2 gene (Com ings et al., 1991), What is the association with smoking for subjects who only smoke? Can be emphasized. Does it focus primarily on genes for ADHD? Nevertheless, results for alcohol abuse / dependency scores were identified for ADHD Many genes were previously identified in the literature as candidate genes for alcoholism. Indicates that they are associated. 13.Study of multiple phenotypes in a single group of subjects Common in behavioral genetics studies A common strategy is to treat individuals with “pure” disorders, few or no co- Recruiting individuals who have no diagnosis, and subjects with or without the diagnosis Is to divide the evaluation into two. Such research has two reasons. You may lose ability. First, individuals with many co-existing states have higher genetic It is likely to have an overall level of load. Therefore, to identify genes Ability increases. Second, by screening for a wide range of behaviors Allows many different disorders to be investigated in the same group of subjects. This This is shown in the current study. Since TS is associated with many co-existing states, (C omings and Comings, 1987a; Comings, 1995a; Miller et al., 1996); Allows testing of all related subjects for differentially related genes so is there. This result identifies unique combinations of genes for different phenotypes. Has been shown to be even more feasible. This is useful for creating multiple DSM-IV diagnostics. And development of multiple quantitative traits in a single group of subjects with high rates of co-morbidities Suggests the use of structured interviews to allow for In each case, rather than accumulating many DNA databases, for a range of obstacles Could be a much more effective approach to finding the gene for   14. Risk factors versus diagnosis and predictability. General assumptions about polygenic inheritance One is that the genes involved act only as risk factors, and In contrast, it is not possible to use genetic testing in a diagnostic manner. And However, the percentage of variation explained by the additive effect of the gene As r increases, so does r, and with it the predictability increases. AD The final r for the HD score of 0.37 uses this set of genes This means that the predictability of the ADHD score is This indicates that it was up to 37%. By adding more genes Therefore, an r value twice as large as this can be obtained. DNA chip technology is available Thus, the number of genetic tests that must be performed is no longer an issue. As shown in FIG. 7, individuals without signs of ADHD vs. individuals who meet the DSM-IV criteria for ADHD The distribution curve of the number of related genes for shows a large overlap, The differences that are present are highly significant. Double or triple the number of genes to add This can eventually result in curves that have little overlap. The inventor Believe that the addition of the gene further enhances diagnostic power.   15. Iteration. Iteration is a valuable gold standard in linkage and association studies As is the case, MAA technology should also be the standard for replication. Number of subjects Variance, composition of proband by severity, ratio of control to subject, quantitative score , And other factors are all final r^TwoValue with the effect of the particular gene itself Is expected to change independently. Apart from these factors, we have: Predict varying levels of repetition. The highest level is when the same set of genes Is additive or subtractive in different groups of subjects and the curve Are similar. Ability to produce similar phenotypic effects of different genes But, As one of the hallmarks of polygenic disorders, we believe that the level of this repetition Unlikely and unpredictable, and different studies Expected to show that a set of genes and curves with different slopes are involved I do. This was confirmed by a split sample test (FIG. 6).   The second and more realistic standard of repetition is that most But not all of the additive genes are also additive for groups of repeats, and T^TwoValues and levels of significance increase as more genes are included But the slope of the curve for different genes may vary. It is the standard of restoration. At this level, the relative importance of groups of genes is repeated. Is also expected. Therefore, adrenergic genes are compared in ADHD While more important than serotoninergic genes, This study, which is more important, should be repeated. This is in ADHD The importance of noradrenergic genes is repeated in both samples In a split sample test. The ultimate level of MAA technology iteration Is caused when it facilitates the identification of genes involved in polygenic disorders.   16. Technical issues. Most important aspects of additive related technologies are covered However, there are some aspects worthy of emphasis. We have established that I feel that quantitative traits are favorable for several reasons. That is, the control is tested It needs to be evaluated for the same trait as the body. This is important. why Then, in our experience, both the control and the subject This is because they may have In addition, analytical power is tested across the full range of quantitative traits. If greater, greater. For maximum analytical power, the number of controls should be The number of subjects that should be approximately equal to the number or have a low score Can be approximately equal to the number of subjects with high scores.   Final r and r^TwoValues are order dependent to unambiguously identify subtractive genes. Not added, so that the gene with the largest positive association is entered first. It may be necessary to change the order in which the genes are placed. The first gene is r Is r^TwoIt is difficult to identify a subtractive gene without an appropriate increase in the value of is there.   17. Therapeutic and pharmacological implications. Its ability to identify related genes and its The last aspect of MAA technology, based on its ability to measure its relative importance, is therapeutic and And its potential to lead pharmacological interventions. For example, four adrenalines Gene is the final r for the ADHD score.^TwoAccounted for 40% of the value Observation is adrenergic α_TwoDrugs acting on receptors may be And value. Clinical research is indeed the treatment of ADHD. Adrenergic alpha_TwoClonidine and guar receptor agonists Supports the efficacy of guanifacine (Hunt et al., 1985).                                 Example 14 Dietary supplementation of chromium picolinate and chromium nicotinate to treat obesity   In this study, chromium picolinate was the most interesting but under the best conditions Chromium nicotinate tested (in combination with exercise training) Preliminary data on this was also considered valuable. Young, obese woman vs This study of the effect of chromium supplementation had two purposes. The first is picoline Chromic acid supplementation alone favors body weight and composition, glucose tolerance, and plasma lipids And whether these effects are enhanced by exercise training Is to determine if it can be done. The second is pairing with exercise training To provide data on the effectiveness of combined chromium nicotinate supplementation You.   Method. The subjects were 43 healthy, sedentary, obese women. varied The statistical cut-off rule for obesity is used for obesity, For obesity, obesity is the recommended percentage of body fat for young women (20-25% Fat is recommended (Blackburn et al., 1994)). Justified. We believe that some of our population is slightly moderately obese. Recognize that Before accepting, use the questionnaire to determine the health status of the subject Attitudes and patterns of activity were determined. Subjects who record a health problem also No subject recorded drug prescriptions for the condition. Ages from 18 to 35 The mean was 24.4 ± 0.70 years. Initial weight is 50.8-96.1 kg Range, with an average of 71.3 ± 1.9 kg. Determined by hydrostatic weight measurement Percent body fat ranged from 25.0% to 45.0% with an average of 33.0% ± 0.91 Met. Early VO_TwoThe max value ranges from 1.53 to 3.30 L / min, the average value is 2.38 ± It was 0.13 L / min. Each subject signs an informed consent form Earlier, I was informed about the potential risks and benefits associated with participation. Research In Approved by the Institutional Review Board of the University of Texas.   Experiment design. Subjects were treated in four treatment groups: pi without exercise training. Exercise training with chromium choline supplement (CP) and placebo (E / P ), Exercise training with chromium picolinate supplementation (E / CP), and Exercise training with chromium nicotinate supplementation (E / CN) One was randomly assigned. The treatment period was 9 weeks. Of the menstrual cycle No effect control experiments were performed. Pre-surveys and post-tests are provisional. Performed at different stages of the regular 28-day menstrual cycle, this effect, if any, Are also randomized among all study participants and therefore do not affect data Should have been.   Chromium supplements and placebo tablets are available from Shaklee, Inc., USA (San Francisco). , CA) and coded bottles each containing 100 tablets Entered and sent to researchers. Subjects were chromium picolinate (200 μg), nicotine 16 tablets containing chromic acid (200μg) or placebo (inactive ingredient) Was given weekly. Subjects are treated every morning for the duration of treatment and post-test. And one tablet each night (resulting in subjects receiving chromium supplements Oral dose of 400 μg daily). Subjects are treated weekly I was required to return the tablets. Drug coverage is determined by counting the returned tablets. Was measured. There were no problems with drug coverage.   Exercise training is a cross training with several components Consisted of programs. The first component was step aerobics . This is for upbeat music, 12-24 inch height benches, and participants Fingers through a series of movements designed to provide a whole-body aerobic workout This is a type of aerobic dance that uses a leading instructor. these 1 In the time class, each exercising subject attends twice a week and qualifies. Taught by the instructor who had. Subjects are on their own bench high You were allowed to choose. The instructor will gradually Increased exercise intensity.   The second component was cycling. Cycling exercises a week Twice, 30 minutes, max heart rate (early VO_Two75% -80% (determined during max test) Performed at target heart rate. Universal Gym Equipmen t, Inc., Cedar Rapids, Iowa). The target heart rate is set at the beginning of each session. Programmed during the ergometer and during exercise, target heart rate Monitor using on-board computer to adjust resistance to maintain number It was done.   The third component was resistance training. Resistance tray Twice a week, the Powercise Fitness System (TruTrac Therapy Products , Inc., Temecula, California). Resistance blurred Five separate machines set up by working equipment were used. This is a chin "Double body" induces foreshortening-only contractions from Nist / antagonist muscle groups Live system. The five machines used were all upper and lower body Exercised the major muscle groups. First, the maximum intensity of each subject Progressively with each iteration (10 lb. Increase) determined by lifting the heavier weight. Once the maximum intensity is determined Once, the training weight is automatically set to 50% maximum intensity and the subject is Coached through three sets of 15 repetitions on each machine did. Subjects should follow a pacing light that allows approximately 1.5 seconds per contractile contraction. Was. The rest time between sets was 25-28 seconds. Time between machines is strictly controlled I didn't control. Subjects completed three additional sets of 15 repeats throughout the study. While being encouraged to increase the weight to lift, and recorded that increase . Subjects should also perform three sets of 20 “abdominal crunches” (sit-ups) Was instructed.   All training sessions are led by at least one investigator Was. Attendance, heart rate during cycling training, and resistance training Recording parameters (lifting weight and completion of repetition and setting) Recorded. Subjects were required not to change their diet during the course of the study.   Experimental protocol. Health-o-Meter body with a sensitivity of ± 200 g during the week before the start of treatment Using a weighing scale (Continental Scale Corporation, Bridgeview, IL) Subjects were weighed at various times and hydrostatically weighed (Behnk e et al., 1974). VO_Twomax, modified Burke protocol The invention uses a treadmill to remove the sucked volume and Measured and determined as previously described for their laboratories (Yaspelkis et al., 1993). Specified. Fasting blood samples were taken on two separate days and oral glucose Load test (OGTT) was subsequently performed as described.   Replenishment and exercise training during the 9 week treatment period are detailed above I went as I did. At 9 weeks of treatment, all pre-survey measurements were repeated. Treatment The tests were performed in the same order both before and after. Refill and exercise tray The training continued throughout the post-test period. Exercise training All subjects given a step aerobics session two days prior to the posttest OGTT And rested the day before the exam, resulting in the last exercise and OGTT It took about 40 hours between the two.   Sample collection and analysis. Plasma for hormone and substrate analysis Between 7 am and 9 am after a 12 hour fast without in or nicotine Obtained. Blood (10 ml) was collected via venipuncture of the antecubital vein. Oral glucose Determination of glucose and insulin response to blood stress Went on the same day as one of Subjects received 100 grams of dextrose (Tru-Glu 100 Range / carbonated, 10oz. Room temperature drink including Fischer Scientific, Pittsburgh, PA) Food, and a blood sample (3 ml) before and after ingestion 15, 30, 60 21-gauge indwelling venous catheter in the antecubital vein after 90, 120, and 180 minutes (Baxter Healthcare, Deerfield, IL).   All blood samples were prepared with 250 ml of ethylenediaminetetraacetic acid (EDTA) (Sigma Chem ical Company, St. Louis, MO). A whole blood sample from a basal sample Recoat (200 ml) with an affinity resin column, colorimetric determination, endpoint procedure (SigmaD iagnostics, St. Louis, Mo.) for the determination of glycosylated hemoglobin used. Centrifuge remaining sample at 1,000 xg for 15 minutes; then remove plasma And frozen at -20 ° C for subsequent analysis. Insulin concentration on the radio Determined by immunoassay (ICN Biomedicals, Inc., Costa Mesa, CA) . Plasma samples were analyzed for glucose, triglycerides, and total cholesterol. And analyzed by an enzyme assay (Sigma Diagnostics, St. Louis, Mo.). HDL -C was determined enzymatically after precipitation of LDL-C and VLDL-C (Sigma Diagnostics, St. Louis, MO.). LDL-C has the formula: LDL-C = (total cholesterol) − (HDL-C) − ( (Triglyceride / 5) (Sigma Diagnostics, St. Louis, MO). Standards were used for each assay to assess consistency. All samples Was used in duplicate and each subject sample was used sequentially.   Statistical analysis. Multivalent ANOVA for before and after values across all treatment groups Used for each variable. Before and after values and time points in OGTT Treated as returned measurement. If a significant F value (p <0.05) is observed, An analysis was performed to determine where these changes occurred. Empirical significance (p <0.05) was used as a criterion for further testing. Post hoc exam , Depending on the nature of the data, to measure ANOVA or Fishers PSLD (p <0.05) Repeated. Using these low stringencies, small sample sizes, and Therefore, due to the limited statistical design power, the opportunity to make Type II errors Protected. Analyze the Statistic Package for Social Sciences (SPSS) software Performed using firmware, version 6.0 for Macintosh.   result. Subjects participating in exercise training should be Completed 90.0% (± 2.2) of the training session. Difference in medication rate between treatment groups There was no difference. Heart rate during cycling is constant HR_max75 and 80% of Was between. Heart rate during step aerobics is very high, 175-190 beats / min (HRI_max85-95%). VO_Twomax is true for all treatment groups It didn't change.   After treatment, there was a significant increase in body weight in the CP group and body weight in the E / CN group. There was a significant decrease. Contains percent of body fat, fat mass, or fat There were no significant changes in mass. Does not contain fat in E / P group Mass is significantly higher both before and after treatment than in all other groups Was. An insignificantly higher initial weight in the E / P group was associated with a higher fat-free mass. It is worth noting that it can almost completely contribute to the crispness.   Significant in pre- and post-basal plasma glucose or insulin levels There were no differences. Glycosylated hemoglobin also does not change after treatment Was. Glucose for each treatment group during the 9 week treatment period before and after treatment Glucose and insulin response curves were obtained from a 3-hour oral glucose tolerance test. I did it. Subjects should receive chromium replacement (CP), exercise training and Placebo (E / P), exercise training and chromium picolinate (E / CP) Or exercise training and chromium nicotinate (E / CN).   Chromium supplements (CP), exercise training and placebo (E / P), Exercise training and chromium picolinate (E / CP) or exercise 9 in subjects receiving chromium training and chromium nicotinate (E / CN) Glucose negative from a 3 hour oral glucose tolerance test before and after the weekly treatment period Comparison of the area under the load curve or glucose curve was significant for both groups. Did not show any effect. Similarly, CP (p = 0.433), E / P (p = 0.087), or E / CP (p = 0.110) There was no significant improvement in the insulin response curve after treatment. Only Insulin response 60, 90, and 120 minutes after E / CN treatment and oral glucose load. There was a significant decrease in the response curve, which had a significant decrease in the overall insulin response. (P = 0.041). The area under the insulin response curve for E / CN treatment also It was found to be significantly reduced after training. Triglyceride, total cholester Significant differences between pre-treatment and post-treatment samples for roll, LDL-C, and HDL-C No differences were found.   Consideration. Our study shows that chromium picolinate supplementation in young obese women The effects of drug, exercise training, or both were compared. The data also On the effect of chromium nicotinate supplements combined with exercise training Collected. Because in vitro studies have shown that chromium nicotinate It suggests that the factor may be effective to change as well.   Body weight was significantly increased in the CP group after treatment. This is an important finding. What Chromium picolinate is often promoted as an aid to weight loss Because it is. Our results show that without exercise, picolinic acid Rom supplementation may not only be ineffective in causing weight loss , Indicating that it can result in weight gain. Weight gain was measured in previous studies with chromium replacement. Have not been found (Kaats et al., 1991; Page et al., 1991; Rials, 1979). this Is likely to be the subject's diet and activity pattern, as well as different genotype patterns. (Ie, the carrier for the DRD2 A1 allele versus the carrier for the DRD2 A2 allele) Is not controlled. Also, our problem group (young, fertilized) Woman) has not been previously studied; this may explain the difference in findings . Similarly, the amount of chromium administered (400 μg / d) in this study Twice the amount studied. At this concentration, chromium enhances weight gain It is possible that lower concentrations may have an inhibitory effect, while lower concentrations may have an inhibitory effect.   No significant changes in body weight were observed in the E / P or E / CP groups. This This is because weight loss is often not observed after 9 weeks of exercise training. Confirm previous work (Stefanick, 1993) showing that However, E / CN group There was a significant decrease in body weight. To the inventors' knowledge, this is Chromium nicotinate supplementation combined with size training is effective in weight loss This is the first study that suggests that this may be an effective means.   After treatment, the relative body fat, fat mass, or fat-free mass There was no significant change. In terms of body weight, the results of this study and previous studies Discrepancies between the study population, uncontrolled diet, and activity patterns, And / or may be due to differences in the amount of chromium administered.   VO_TwoThe max level did not increase significantly after the training period. This is a trial May have been due to the lack of specificity of the test: maximum pre- and post-test Training on a cycling and aerobics It became. In addition, the load component of the training program is aerobic Perhaps they have shielded or reduced the formation.   Basal glucose levels did not change significantly in any of the treatment groups. this Results show that chromium supplementation (Abraham et al., 1992; Wilson et al., 1992) in a euglycemic population 95) and other exercise training (Wallberg-Henriksson, 1992) Match The response of plasma glucose levels to an oral glucose load is E / It was significantly higher in the CP group before and after treatment when compared to the P group. group Means the inverse proportional relationship between the fat-free mass and the glucose area under the curve. This implies that the larger fat-free mass is the absolute amount of glucose Suggests that faster disposal is possible. However, individual data Showed that there was little correlation between the two factors (r = -0.26).   No treatment effect was observed for the glucose response to an oral glucose load. won. With respect to basal glucose levels, subjects initially receive an oral glucose After loading, it showed normal glucose levels. 6 weeks for glycosylated hemoglobin Of plasma glucose levels over a period of time but did not change after treatment Was. Basal insulin levels were initially within the normal range, but after treatment any There was no significant change in either group.   Insulin response to oral glucose tolerance is significant after treatment in E / CN group Decreased to. Improvements in insulin response have been shown previously in hyperglycemic patients (Djordjevic et al., 1995). Significant changes in the insulin response were No observation was observed in the size-trained group; won. Because of the previous decrease in exercise training, (Heath et al., 1983; Mikines et al., 1989; Sharma, 1992; Wallberg-H. enriksson, 1992). However, this decrease has been found to be very short in duration. (Heath et al., 1983; Mikines et al., 1989). Accordingly, we have found that glucose stimulation No reduction in the response of insulin to insulin could be confirmed in these subjects May have been due to the rapid decay of the improved insulin action. E / Exercise training effect on insulin action in P and E / CP groups Whatever the cause, the exercise training and Nico It suggests that a combination of chromium phosphate may be beneficial.   Basal plasma lipids did not change with treatment. Few abnormal early lipid levels Subjects with normalization headed for normalization after treatment, but these changes were not significant. It was interesting to note that there was no.   In summary, high levels of picoli without exercise training at the same time Chromate supplementation caused significant weight gain in young obese women On the other hand, exercise training combined with chromium nicotinate supplementation Includes significant weight loss and lower insulin response to oral glucose tolerance Have brought some potentially beneficial changes. We have found that the high (400 μg / d ) Supplemental amounts of chromium picolinate are associated with weight loss in young obese women Exercise contraindication with chromium nicotinate supplementation Provides some protection against CAD and NIDDM through risk factor modification. Conclusion that exercise training can be more beneficial than exercise training alone I do.   Chromium supplementation has various risks for coronary artery disease and non-insulinic diabetes. Factors such as body weight and composition, basal plasma hormone and substrate levels, and oral Response to the Rucose load). One study found that the effect of chromium was one. Young obese woman at 400 μg per day, with or without exercise training Were tested for these risk factors in gender (Grant et al., Med. And Sci. Sport. s and Exercise, 29: 992-998, 1997). Chromium picolinate (CP) supplementation Chromium nicotinate (CN) supplementation Exercise training combined with replenishment can result in significant weight loss and oral This resulted in a decrease in insulin response to Lucose challenge. The present inventors have Bell chromium picolinate supplementation bans weight loss in young obese women It concludes that it shows an annihilation. Furthermore, our results show that chromium nicotinate supplementation Exercise training in combination with exercise training alone Suggest that specific CAD and NIDDM risk factors may be modified I do.   After treatment, a significant increase in body weight in the CP group and body weight in the exercise CN group There was a significant decrease in weight (at least P = 0.05). Percent body fat, fat There were no significant changes in amount or fat-free mass. Exasa Fat-free mass in the Is-Placebo group was treated in all other groups Significantly higher both before and after. Furthermore, unlike the CP group, exercise CN Treatment resulted in significant decrease in insulin response at 60, 90, and 120 minutes did. After an oral glucose load, this was significant in the overall insulin response curve. Significant reduction (P = 0.041).   Data from this study show high levels of data without concurrent exercise training. Chromium picolinate supplementation causes significant weight gain in young obese women Exercise training combined with chromium nicotinate supplementation Include significant weight loss and a lower insulin response to oral challenge. Suggest that some beneficial changes have been made. This data is high (400 μg d^-1) The use of supplemental amounts of chromium picolinate can reduce body weight in young obese women In combination with chromium nicotinate supplementation Exercise training is more beneficial than exercise alone in losing weight Suggest possible. Combined allele of OB / gene and DRD2 gene Offspring frequency accounts for as much as 22% of obesity variability in young obese women, and The type affects the effect of chromium salts on weight loss specific to this population, Can have an effect of chromium on weight loss in children (Comings, 1997). table RDS-related disorders as described in Table 4, and especially obesity as described in Table 6. A chromium salt (eg, chromium nicotinate) of a composition for treating a related disorder. And / or chromium picolinate) may help maintain weight loss. Is intended.                                 Example 15 Chromium picolinate is TAQI dopamine D_TwoReceptor A_TwoBody as a function of allele                       Induces changes in the composition of   Method. In this study, we identified dopamine D_TwoReceptor (DRD2) and Standard PCR for both dopamine transporter gene (DAT1)^TMTechnology Utilized, 100 subjects were genotyped (Blum et al., 1997). Subject is weighed Body weight and percent body fat using a densitometer. Was. Subjects were placed in a placebo group according to the method developed by Kaats et al., 1998. And chromium picolinate (CrP) group (400 mg per day).   result. In the literature control, the TaqI DRD2 A1 allele had 714 patients. Present in 26% of test subjects (185/714), and 30 very well rated Sue It was present in 3.3% (1/30) of the par control. By χ-square analysis, these 2 A significant difference was revealed between the two control groups (p <0.006).   DRD2 A1 allele is 67.4% (58/86) in obese subjects with ≧ 28% body fat In 61.5% (8/13) of obese men with ≧ 28% body fat, and ≧ 28 % Were present in 68.5% (50/73) of obese women with body fat. DRD2 A1 confrontation Genes are present in 65.3% (49/75) of obese subjects with ≧ 34% body fat; ≧ 34% body fat In 62.5% (5/8) of obese men with fat, and with ≧ 34% body fat It was present in 65.7% (44/67) of full women. The DAT1 10/10 allele has 91 In 37.4% (34/91) of control subjects, 4 of obese subjects with ≧ 28% body fat 7.7% (41/86), ≧ 28% in 38.5% (5/13) of obese men with body fat, and ≧ 28 It was present in 49.3% (36/73) of obese women with% body fat. DAT1 10/10 allele Had 46.7% (35/75) obese subjects with ≧ 34% body fat, 37.5% (3/8) of fully male and 47.8% (32/67) obese women with ≧ 34% body fat Existed. Chi-squared analysis shows that the difference between the TaqI DRD2 A1 allele and morbid obesity Significant association compared to either literature control or supercontrol It became clear if you did. Table 67 shows that men with significant associations ≤28% body fat Literature controls (コ ン ト ロ ー ル square = 62.6, df = 1, p = <. 0001) for both ); And super control (χ square = 36.6, df = 1, p = <. 0001) ). Significant association was found in men with ≤34% body fat Literature controls (χ square = 50.6, df = 1, p = <. 0001) for both ); And super control (χ square = 33.0, df = 1, p = <0.000) 01). Literature control for men with ≤28% body fat Effect (χ square = 8.31, df = 1, p = .004); About trawl (χ square = 18.6, df = 1, p = <. 0001); and ≦ 28% body fat Effect of women with a control compared to literature controls (χ square = 57.34, df = 1, p = <. 0001); and for the super control (χ square = 36. 11, df = 1, p = <. 0001). Literature control for men with ≤34% body fat (Χ square = 5.46, df = 1, p = .02); and supercontrol For roll (Chi = 16.6, df = 1, p = <. 0001); and have ≦ 34% body fat Of women compared with literature controls (χ square = 46.73, df = 1, p = <. 0001); and about super control (χ square = 32.38, df = 1 , P = <. 0001). In contrast, in this morbidly obese population, D No association found for any combination of alleles for AT1 gene Was not. Literature controls for both men and women with ≤28% body fat When compared to rolls (χ square = 2.27, df = 1, p = .132), and ≤ 28% body fat For males who have, compared to literature controls (χ square = .02, df = 1, p = .89), and women with ≤28% body fat compared to literature controls Case (χ2 = 2.73, df = 1, p = .098). For men and women with ≤34% body fat In comparison with the literature control (χ square = 1.75, df = 1, p = .185) and And ≤34% body fat compared to literature controls (χ squared) = .01, df = 1, p = .96) and literature control for women with ≤34% body fat (Χ2 = 2.02, df = 1, p = .16).   Using a statistical technique called logistic regression analysis, more than 34% When comparing the super control with body fat and all cases, DRD2 A1 Alleles account for 45.9% of the variance, which is statistically significant (χ square = 43.47, df = 1, p <.0001). In contrast, DAT1 ( 10/10 alleles) account for 3% of the variance, and represent the variance of this population under study. There is no statistically significant contribution.   For CrP data, the samples were in two independent groups; A1 / A1 or A1 / A2 alleles Divided into groups with any of the genes, and groups with only the A2 / A2 pattern Was. Each of these groups was treated with placebo and treatment for various weight change measurements. The differences between the means were tested separately. These measurements provide a measure of the change in fat weight. -Cent, change in fat weight, change in weight, change in mass without fat, fat weight Percentage change, body composition index, and weight change in kilograms, from calculations became. Differences between the mean of placebo and treatment groups were determined using the t-test for independent groups. And tested statistically. For statistical significance, set the α criterion to p = 0.05 Were determined for these comparisons. Any p-value less than 0.05 is Expected to show a statistically significant difference in mean between placebo and treatment groups You.   T-test analysis shows that the carrier of the DRD2 A2 allele It became clear that it was more responsive due to the effect of CrP than the rear. Fat weight Change (p <0.032), change in body weight (p <0.011), percent change in body weight (p <0. 035), and measurements of weight change in kilograms (p <0.012) were all significant. For any of the parameters for subjects with the DRD2 A1 allele. And no significance was found.   Consideration. These results indicate that the dopaminergic system, in particular, D_TwoReceptor density Provides significant differential therapeutic effect of CrP on weight loss and changes in body fat Suggest to do. This indicates a relationship between gluttony and the A1 allele of the DRD2 gene. It becomes even more significant when considered (Blum et al., 1995). A2 DRD 2 Positive carrier response maintains the positive metabolic effects of CrP, In contrast, it is our intention that this is not the case for A1 DRD2 carriers. What If so, an increased carbohydrate glut can help CrP reduce weight loss and changes in body fat. This is because the effect is shielded. These data are also used by A1 DRD2 carriers. Combination of CrP as another chromium salt with amino acid precursor therapy Suggests that should result in reduced appetite and significant weight loss (Blum et al., 1997). Furthermore, the present inventors have now observed the body composition with CrP administration. The combined effect of the treatments is determined by the expected patient genotyping prior to treatment. We propose that it can be clarified. Chromium picolinate or chromium nicotinate The reason for the observed effects is that chromium salts affect primary metabolic parameters Amino acids affect dopamine-lowering deficiency, This is because it reduces the appetite for sweetness.                                 Example 16 Amino acid and herbal composition for enhanced attention processing              Object: Potential efficacy in attention deficit hyperactivity disorder   We have identified dopamine D in humans._TwoReceptor gene polymorphisms and brain electricity An association between physiological abnormalities was observed. In this regard, a weighted linear trend analysis (Weighted linear trend analysis) shows DRD2 A2 genotype and Event association in the presence of the DRD2 A1 allele compared to impaired use (SUD) [p <0.0001] The significant worsening effect of potential (EP) was revealed. Reduction of P300 wave of evoked related potential (ERP) Little size and latency have long been associated with alcohol and drug dependence. Was. We also found that significant prolongation of P300 latency was associated with three risk factors: (1) parent SU D, (2) drug dependence (ie, cocaine dependence), and (3) carbohydrate glut It was found that they were correlated. We also have two DRD2 A1 alleles (A1 / A1). One copy has an extended latency of P300 waves compared to the A2 form of the gene (A2 / A2) It was found that it significantly correlated with gender. In addition, the size of P300, alcohol poisoning And SUD correlated with family history, and Hill (University of Pittsburgh) A significant correlation with a DRD2 A1 allele of size 00 was also found. These conclusions Results include attention processing and potential RDS-related actions (ie, SUD and ADD / ADHD). DRD2 A1 allele in non-behavioral pathophysiological phenotypes involved in brain function Suggest a role for P300 abnormalities are well documented, but once thought It is noteworthy that it was not as specific to substance abuse as it had been. These In mixed ADD, schizophrenia, delirium, obesity, and other psychological disorders General.   Many therapeutic interventions involve potential abnormalities induced, as well as spectral analysis (eg, For example, cholinergic agents, choline elastase inhibitors, dopaminergic and Serotonergic drugs, stimulants, trace elements, diet (low-refined carbohydrates), cranial stings Intense, biofeedback, and its implications for different non-specific approaches Others) have been shown to improve.   Dopaminergic function is associated with reduced D2 receptors, potentially in brain electrophysiological abnormalities. Therapeutic measurements are related to brain D_TwoEnhances receptor function May exist in technology developed for Dopamine D_TwoGene of gene products related to receptors Currently, TaqI A1, TaqI B1, and other alleles that cause dopaminergic deficiency It is significantly reduced by offspring. At the moment, regarding gene repair, Although there are no known techniques for restoring receptor deficiency in a permanent manner, A particular part of the invention is D_TwoB_maxTo overcome this genetically induced decrease in Present the possibilities. Bulmocriptine, and N-n-propylnor apomorphine D by agonists containing_TwoUp-regulation of dopamine receptor observed (Fitz et al., 1994). In addition, changes in mRNA were not detected after agonist treatment. It did not seem to explain the increase in Puter. Instead, use cycloheximide (tan Studies with inhibitors of protein synthesis have led to increased protein synthesis (gene expression). Up-regulation), and unreduced proteolysis It is suggested to be responsible for up-regulation by min-agonists. This Utilizing the logic of the present invention, the present invention relates to enkephalinase inhibition (D-phenylalanine) Coupled use of potentiation of synaptic dopamine release via_TwoReceptor increase Breeding D_TwoFor chronic occupancy or transfected HEK-293 cells To promote up-regulation as shown in this Further form the basis of the present invention.   Electrophysiology and neurotransmitter function. Brain electrical activity mapping (QEEG and cortex Evoked potentials can be assessed in a wide variety of subjects (neurosis (Braverman et al., 1990; Chr. istian et al., 1994; Blum et al., 1995), criminals (Lovinger et al., 1995; Seiden et al., 1995). , Depression (Hudson, 1995), Alzheimer's disease (Scourfield, 1996; Lawford, 1995). ), AIDS (Meiswanger et al., 1995), response to ADD / ADHD and its prescription (Kokkevi 1995; Nunes et al., 1995; Yoshida, 1984), and SUD (Gilman et al., 1990; Morrow). Et al., 1992; Brown et al., 1994; Comings et al., 1996; Neshinge et al., 1991). Revealed the presence of few neurological changes (Porjesz et al., 1987). Drug is God Deep limbic structure (located in temporal lobe) (Yoshida et al., 1984; Gilman et al., 1990); It is well known to lead to physical abnormalities. These topological changes are caused by drug use. Important marker or ingredient that motivates the desire of the individual to seek for Can be The limbic arousal phenomenon is associated with both desire and withdrawal symptoms in SUD subjects. (Ballenger et al., 1980). In addition, SUD Pre-morbid depression is associated with subsequent Alzheimer's encephalopathy, concurrent ADD / ADHD, And prophylaxis of probands for other psychiatric disorders that may originate in the temporal lobe. Can be treated. Temporal lobe abnormalities in brain mapping correlate with reduced metabolism in PET scans In this regard, this is a temporal lobe attack between attacks that also have hypometabolic Similar to disabled patients (Adams et al., 1993). The DRD2 A1 allele is a PE in the frontal lobe It has been reported to be associated with low glucose metabolism as measured by T-scan (Noble et al., 1997). This is because hypometabolism leads to dysfunction in the frontal lobe of the brain. Low dopamine D_TwoSuggests that it is related to the receptor. Many papers, SUD, Excitement (Goldstein et al., 1994) or electrophysiological instability (this is Position and spectral analysis abnormalities). further , Both cocaine and ethanol cause excitatory responses or electrophysiological instability Induced, and triggered on an acute basis, most likely via dopamine release. Temporarily correct the potential abnormalities. Recovering a drug abuser requires that drug use Even after being interrupted, it still had a low P300. Only P300 activity partially recovered, It also indicates the use of predated substances with genetic characteristics, which is Leads to abuse of cocaine or heroin similar to that observed in survivors (Gil man et al., 1990).   We believe that drug addiction significantly worsens potential pre-morbid conditions. And strongly suggests a genetic environment interaction. These electrophysiology Releases dopamine to the nucleus accumbens, which is used to relieve mechanical disorders, especially with drugs Self-prescription or behavioral behavior of the drug (ie, Unfortunately, alcohol, nicotine, sugar, sex) worsens brain failure Result.   Additive effects of different dopamine genes. Up to 4 generations of ADHD / ADD and RDS genotypes Three dopaminergic genes (DRD2, DβH, and A summary of recent studies by the present inventors involving the DAT1 gene) is provided herein. It is shown. Taken together, these results indicate that ADHD, TD, and other disorders It is inherited in a genetic manner and has extensive associations caused by shared genes. Of some diseases (RDS) caused by common alleles in the population , Caused by genes that are additive in its effect, Molecule to the idea that it is caused by a gene that disrupts the dopamine system Provide support at the genetics level.   The dopamine gene in probands with attention deficit / hyperactivity disorder (ADHD) and multiple family members Intergenerational research up to 4 generations. Dopamine D_TwoReceptor gene polymorphisms are reported in Reward Deficiency Syndrome (RDS) or many related impulses Associated with impulse-addictive-compulsive behavior; ADH D and V of dopamine transporter gene (DAT1) associated with Tourette's disease (TD) NTR 10/10 genotype; and also associated with TD and many RDS behavioral paratraits B1 allele of dopamine β hydroxylase gene (DβH).   We have identified 51 subjects in four generations from two multiply affected families. Until genotyped. DNA, PCR^TMAccording to the method (Blum et al., 1997) , Extracted from cheek swabs. Two early probands are injected by many standard devices The patient was diagnosed with ADHD. Subsequently, additional family members also have ADHD and And other related RDS behaviors. All subjects received three dopamine crops The utility genes (DRD2, DAT1, and DβH) were genotyped. All subjects Eighty percent (40/50) of the bodies had DRD2 TaqA1. "Super" Con Compared to trolls (1/30 or 3.3% carried the DRD2 A1 allele) , A significant association with an odds ratio of 116 [95% confidence limit, 13.6-2,575] (Square = 41.1, df = 1, p = 0.00000001, Yates corrected). The inventor Point out the importance of highly screened controls These data are presented for the purpose. Similar but less robust findings , 714 non-alcoholic and drug abuse literature controls (185/714 or 26% had the DRD2 A1 allele) Obtained by the authors when comparing the data. Significant association (χ square = 63.2, df = 1, p = 0.00000001, Yates corrected), but with an odds ratio of 11.4 [95% confidence limit, 5.3 8-24.93]. DA in 91 screened controls The prevalence of the T1 10/10 allele is 34/91 or 37.4%, as well as 51 In the screened controls, the prevalence of the Df3H B1 allele was 2 7/51 or 53%. Significant association (χ square = 7.51, df = 1, p = 0.0061) Controls screened with an odds ratio of 2.64 [95% confidence limit 1.35-5.38] Two family members from ADHD (30/50 or 60%) when compared to roles And DAT1 (VNTR 10/10 genotype). In contrast, non-significance (χ square = 1.27, df = 1, p = 0.259) compared to 0. With an odds ratio of 63 [95% confidence limit 0.28-1.4], the DβH B1 (32/50 or 64%) Found in the carrier. The present inventors report that a single urge poisoning compulsive The DRD2 A1 allele in these subjects as compared to the commonly found 40-50% A high percentage attributed to multiple behavioral side traits, including RDS. In one family, the DRD2 A1 allele was diagnosed as having ADHD. % Of subjects were present.   Present to family members as a co-variate when data is complete Perform linkage analysis using at least one RDS action. RDS behavior in the subject Note that the presence of the DRD2 A1 allele also increases as the number of Deserve. At first glance, the DRD2 A1 allele is distinct from the other two dopaminergic genes. By comparison, at least ADHD and RDS in this currently tested sample There is more information in predicting both actions. Data is currently being processed And further findings indicate that these findings are associated with compulsive addiction compulsive behavior (RDS) and One important side trait, presented on the impact on genetic engineering of ADHD, and discussed Discussed.   Cognition, electrophysiology, and neurotransmitter function. One important aspect of the present invention is that Attentional processing is responsible for “rewards” and other related actions. Affected by alterations in neurotransmitter function, especially in the brain (limbic system) That is. In addition, genetic or environmental factors (drugs, gender, and stress) Dysfunction in the "reward cascade" via the can affect attention processing. Many neurotransmitter pathways are generally ultimately involved in concentration, memory, and cognition However, at least four major pathways are preferred for involvement in the present invention: Rotonin, opioid, GABA, and dopamine. recognition For a brief review of the literature on neurotransmitters and neurotransmitters, see Dopaminergic Systems and Attention Processing Positive for a positive relationship between This relationship activates the dopaminergic system And promote agonist interactions at the dopamine receptor, or Or natural dopamine-releasing compounds can increase attention and concentration in individuals. Support the concept of augmentation.   Dopamine D_TwoReceptor gene polymorphisms are associated with brain electrophysiological abnormalities in humans. Related. This is dopamine D in humans_TwoReceptor gene polymorphisms and brain electricity What we know to provide evidence for an association with physiological abnormalities This is the first study. In this regard, a weighted linear trend end) Analysis is based on DRD2 A2 genotype and co-morbid drug use disorder [SUD] In the presence of the DRD2 A1 allele, a significant worsening effect of the event-related potential (EP) Clarified (p <0.0001). Duncan's Range Test has DRD2 A1 allele SUD with or without significantly worsened EP compared to DRD2 A2 control It was shown. In addition, the present inventors have set out the “super control” of the present inventors. ”(P <0.0000033) and many literature controls (p <0.0021). To see a significant association between severe drug use disorder (SUD) and the DRD2 A1 allele I thought. The reduced magnitude and latency of the P300 wave of evoked related potentials (ERP) Has long been associated with drug and drug dependence. In this study, we found that Significant prolongation of P300 latency was attributed to three risk factors: (1) parent SUD, (2) drug dependence ( (Ie, cocaine dependence), and (3) correlate with carbohydrate phagocytosis (p <0.03) I found that. In this population we also reduced the magnitude of P300. Correlate with family history alcoholism and SUD (p <0.049) but remain DRD2A1 It was found that it did not correlate with the gene. These results indicate brain function and potential DRD2 A1 allele in a non-behavioral pathophysiological phenotype involved in toxic disorders Role.   The purpose of this study was dopamine D_TwoReceptor gene (DRD2) TaqI A1 allele With a drug use disorder (SUD) in humans visiting a private outpatient clinic Was to determine whether it was associated with or without brain electrophysiological abnormalities . D_TwoPotency between the A1 allele of the dopamine receptor gene and alcoholism After some relevant findings from our laboratory (Blum et al., 1990), The loop failed to replicate that observation (Gelernter et al., 1997). The present inventors Suggests two possible reasons: first, alcohol, drugs, and tobacco Poor screening of abuse and other related behaviors, and Secondly, the characteristics of alcohol dependence on the chronicity and severity of the disease. You Sampling error (Blum et al., 1996). However, a review of the literature indicates that the DRD2 gene Many positive associations have emerged, including alcoholism, as well as multidrug abuse, Smoking, Attention Deficit / Hyperactivity (ADHD), Carbohydrate Gyrus, Tourette Disorder, Pathological Gambling, Mind Post-traumatic stress disorder, and RewardDeficiency Syndrome ) "(RDS) (Blum et al., 1996). The association with a group of pessimistic disorders was also revealed. Variations in the DRD2 allele are Very common associated with dopaminergic function, where call dependence is the only sign Variations in latent traits have been discussed (Hill and Ne iswanger, 1997). In addition, "other pathologies" can be used for both control and affected Exclusion from San Antonio, Los Angeles, Duarte, and Pittsburgh (Hill et al., 1997; Blum et al., 1996). Therefore, the chain Or no with-in-family association was found It is the present inventors's point that this was caused by an incomplete understanding of the various phenotypes.   Therefore, to reduce the spurious results, we set out that DRD2 TaqI A1 Brain electrophysiology abnormalities have been used as markers for subsequent association studies in genes. Determined to use a behavioral pathophysiologically non-based phenotype known as Other human association studies with the DRD2 TaqI A1 allele suggested this approach (N oble et al., 1994; Blum, 1994). To date, SU among other vandalism disorders D, ADHD, behavioral disorder (CD), pathological violent behaivior And evoked electricity for many behavioral disorders, including Alzheimer's disease There is a correlation between abnormalities in both (American Psychiatric Association Task Force, 1991).   We have found significant evoked potential abnormalities with SUD and obesity, The present inventors have reviewed the neuropsychiatric and medical clinics of Princeton, New Jersey. Direct correlation of abnormal brain electrical activity with the DRD2 A1 allele in patients visiting patients It was decided to systematically evaluate the potential of Seki. Positive correlation is with pre-morbid genes It can provide important and relevant clinical information for the diagnosis of brain dysfunction based on.   The correlation between DRD2 allelic variation, SUD, and spectral analysis was examined. DRD Visually evoked response (VE) in a representative normal subject with 2 R) Significant probability map (SPM) was determined. Standard deviation (SD) maximum (0.34) and The minimum (-1.00) was calculated as the SPM, and our control group was Standardized BEAM^TM(Brain electrical activity mapping) not significantly different from control . DRD2 TaqI A1 / A2 with left frontal temporal lobe excess negative to 2.92SD without SUD The characteristic brain map of VER in subjects with alleles is Has been visualized. Right anterior temporal lobe abnormalities, indicated by bright blue-white areas, Individuals with movement, palpitations, anxiety, and stress, with or without SUD Representative. DRD2 T with excess negative to 6.13SD in left and right anterior temporal lobe The characteristic brain electrical activity map of VER in SUD patients with aqIA1 / A2 genotype It was visualized by bright white light.   We also have three risk factors: (a) parent SUD, (b) drug dependence (ie, (Cocaine dependence), and (c) P300 latency correlated with carbohydrate phagocytosis (p <0.03) I found an unexpected extension. The present inventors also found that the magnitude of the reduced P300 Correlate with alcohol dependence and SUD (p <0.049), but DRD2 A1 alleles Found no correlation.   Most importantly, due to the weighted linear trend, DRD2 A2 genotype and co-morbidity Effect of event-related potential in the presence of DRD2 A1 allele compared to SUD in rats Was found (p <0.0001). Duncan's Range Test detects the DRD2 A1 allele SUDs with or without have significantly increased EP compared to DRD2 A2 control It was worse.   In this study, 52% of severe SUD patients (N = 29) had DRD2 TaqI A1 alleles. It is worth noting that he had a child. The prevalence rate is based on the inventors' “Normal” controls (alcoholism, SUD, smoking behavior, ADD / ADHD, carbohydrates) Gluttony, pathological gambling, schizoid / avoidant personality behavior ity disorder behavior), violent behavior, and alcoholism. (Excluding active family history, SUD, and obesity) (DRD2 A1 allele prevalence of 3.3% ( 1/30) (has chi-square = 17.47, df = 1, P <0.0000033)) Different. In addition, 714 non-alcoholics, non-SUDs (excluding tobacco), non-His 25.9% of white panic controls carry the DRD2 A1 allele Was. Very strong relationships when compared to non-Hispanic Caucasian SUD probands Runs were found (χ square = 9.44, df = 1, P <0.0021).   To the best of our knowledge, this is the case for patients visiting neuropsychiatric settings. Increasing cerebral electrophysiology in both VER and auditory evoked response (AER) This is the first study to observe a significant association between abnormal DRD2 A1 alleles. You. This genetic proof indicates that individuals who are susceptible to stimulant abuse / addiction Dopaminergic genes and stimulants, along with other studies of electrophysiological disturbances in Further suggests an association with trends in abuse. SUD is the brain mapping parameter Worsening (Braverman et al., 1996; Blum et al., 1995; Lovinger et al., 1995; Seide n et al., 1995; Hudson, J., 1995), and in the event of withdrawal symptoms, That some drug-induced brain electrophysiological damage appears to persist (Scou rfield et al., 1996; Lawford et al., 1995; Neiswanger et al., 1995). Book The inventors believe that co-morbid SUD in psychiatric probands may increase the potential pre-morbid state. Is significantly worsened, and strongly suggests a genetic environment interaction (Ko kkevi et al., 1995; Nunes et al., 1995). To alleviate these electrophysiological disturbances Unfortunately, the self-prescription of illegal drugs, such as cocaine, Exacerbates brain dysfunction with chronic repeated use, especially in the bilateral temporal lobes of the brain You. In addition, reductions in P300 size and prolongation are associated with alcoholism and drug Poisons have been implicated (Yoshida et al., 1984; Gilman et al., 1990). This is Alco Independent of the acute effects of the drug and the drug. Because the knowledge is Because it was a gift of alcoholics who did not use the drug (Morrow et al., 199). 2; Brown et al., 1994). This reduces the size, and prolongs the latency of the P300 wave On the presence of genes that are involved in Reach.   In a global sense, we believe that these observations indicate that dopamine Has important neuropathological relevance supporting an additional role (ie, reward) I think that. Linking DRD2 polymorphisms is associated with dopamine receptor function (Pohjalainen et al., 1996). In 33 Finnish male volunteers, D The TaqI A1 allele of the RD2 gene has an adjusted B relative to A2 / A2 subjects._maxTo Was associated with a statistically significant decrease in K_dWas not significant between groups . This indicates that the number of receptors decreases with A1 / A2 subjects, whereas Evidence that changes in receptor function do not appear to exist Figure 2 shows a regulatory role for 3'-mediated polymorphism in adulthood. In addition, DRD2 knock Utmouth is D_TwoReceptor B_maxSignificant decrease in K_dWithout change in (Grandy et al., 1989). Thus, the regulatory genetic element is a TaqIA polymorphism It can be due to chain instability with sex. Therefore, brain electricity like DRD2 A1 allele Demonstration of polymorphisms of specific molecules that have identified physiological abnormalities has significant clinical utility Should have. Theoretically, from these studies, polymorphisms in dopaminergic systems Are specific brain electrophysiological mechanisms that appear to mediate abnormal behavior (a paratrait of RDS) It appears to be linked to dysfunction (ie, VER and AER).   If these relationships continue to be defined, we are at a particularly high risk. In groups, it may provide a better prevention strategy. In addition, more specific The targeted mode of treatment ultimately, in our opinion, is significant for human behavioral pathology. Derived from these shocking studies.   Subject. A total of 294 subjects were utilized in this study. All of the subjects Were non-Hispanic whites who signed informed consent; this study Has been approved by the Path Research Foundation Institutional Review Board Was. Provide patients with a PATH outpatient private clinic for one year From about 5000 visits from 800 patients visiting, we randomly selected for the study.   All subjects in the SUD group may have an early complete (DSM IV) remission of SUD Clinically established (Brown et al., 1994). Based on our 173 samples Demographic classifications are listed in Table 69. Gender and psychiatric diagnoses were There was no significant difference between all groups. The average age among all groups was evaluated, Not significantly different (p <0.00001). 53.1% of men and 46.9% For this survey of gender selection involving women, age differences were found in psychiatric diagnoses However, no gender differences were found.   Electrophysiology and gene type classification methods. Judgment of selection to determine SUD phenotype Reference and evaluation equipment (cocaine abuse, DSM IV code no. 305.60; cocaine dependent Disease, DSM IV code no. 304.20; alcohol abuse, DSM IV code no. 305.00: Alcohol and alcoholism, DSM IV code number 303.90), the present inventors We used the same methodology as previously reported by the authors (Braverman et al., 1996). Subjects were tested for DRD2 allelic variants (DRD2 TaqIA1 and And A2) were genotyped. Nicolette BEAM^TMUsed for evaluation There were global brain abnormalities, total spectrum abnormalities, evoked potentials (EP, AER, VER) and P300. Brain For a detailed description of this methodology for assessing electrophysiological abnormalities (Braverman and And Blum, 1996). We also genotyped for matched comparison purposes. An uncontrolled P300 control group was included in this study. P300 control The group consisted of 15 male volunteer subjects (no drug, alcohol, and food poisoning). And no psychiatric illness).   Statistical analysis. Classify whole-brain map data as abnormal or normal for statistical analysis did. Specifically, the EEG classifies the spectrum into two types, normal and abnormal, Standardized BEAM using regression of deletions (identical loci) following three independent runs^TM The control was divided into two types based on 2.5 SD. P300 potential is the established normal potential Classified into two types by 10dv (Neshinge et al., 1991), and the latency of P300 is two types with 350ms Classified. This value is 300 ms + the average age of the control group (Lexicor, Inc., Bo ulder, a criterion developed by Colorado, and every 18 years Increase about 1.25 ms in P300). Complete description of statistical methodology The publication has been published previously (Braverman et al., 1996). In addition, we have: Use the Duncan's Range Test to compare paired means. Used. Alpha levels were set at 0.05 for significance.   Kantroll^TM1Enhances attentional processes in healthy subjects: enkephalinase A substitute for cocaine with inhibitory properties. This is a specific mixture of amino acids, Ka ntroll^TMOf the potential (ERP) associated with cognitive events associated with behavior in humans This is the first report of the effect of daily oral intake on the subject. For normal young adult applicants And cognitive ERP are two computerized visual attention tasks (Spatial Ori entation Task (SOT) and Contingent Continuous Performance Task (CCPT)) Triggered by a response to Here, each subject was tested before oral ingestion of amino acids. And served as its own control for the test after 28-30 days. ERP The statistically significant amplitude enhancement of the P300 component of Kantroll for both tasks^TMAfter Was seen in The changes observed in this study were Enhancement of neurophysiological function, amino acid supplements (Kantroll^TM) After oral ingestion Behaviors of the compensation deficiency syndrome (ie, ADD / ADHD, drug use disorders, Strongly suggest that it could be a basis for facilitating recovery Was.   The most intriguing findings in neurobiology are brain function and mood regulation. And many important neurotransmitters (eg dopamine, norepinephrine) , Epinephrine, serotonin, melatonin and glycine) Could be dramatically affected by circulating concentrations of amino acid nutrients (eg, For example, Wurtman, 1983). Each precursor amino acid is L-tyrosine (or L-tyrosine). -Phenylalanine), L-tryptophan and L-threonine. this All of these neurotransmitter synthesis systems exhibit two important features. First, neurotransmitters The amino acids from which quality is synthesized are among the nine essential amino acids: histidine , Isoleucine, leucine, lysine, methionine, phenylalanine, threo Nin, tryptophan and valine (tyrosine is synthesized from phenylalanine) Is). Second, the first step in the synthetic pathway uses an unsaturated enzyme. this As a result of these two characteristics, daily intake of these amino acids is It can drive quality synthesis. This is due to the large number of adjustment feedback mechanisms Although not a linear relationship, it was shown to be a highly significant regulatory pathway (He rnandez-Rodriques and Chagoya, 1986; Wurtman and Fernstrom, 1976; Wurtma n et al., 1981).   Elaborate measurements of brain chemical turnover (including microdialysis measurements) in animals Demonstrated altered neurotransmitter production after body amino acid loading (Hernadez et al., 19 88). Complementary after systemic and direct delivery of precursor amino acids to the central nervous system Behavioral changes have been demonstrated in animals (Blum et al., 1972). Specific L-amino acids Is a neurotransmitter and neuromodulator precursor, its racemic form D-A Mino acids also have biological activity. In particular, D-phenylalanine and D- Isine reduces the degradation of opioid peptides, which is associated with the regulation of mood and behavior. Central (Blum et al., 1987; Carenzie et al., 1980; Della Bella et al., 1979; Ehrenpr eis et al., 1979).   Neurotransmitter action forms the neurochemical basis of behavior, and its confusion is It may be central to various psychiatric and behavioral disorders. Against toxic disorders Their contribution is also the focus of findings to consider. (Koob and Bloom, 1988; Wise and Bozart, 1985; Blum et al., 1990; Blum and Kozlowski, 1990; And Brown, 1982). Specifically, dopamine, serotonin, norepinephrine, γ Aminobutyric acid (GABA), glutamine and opioid peptides are toxic To play an important role in alcohol, heroin and cocaine abuse) (Blum et al., 1977; Geller et al., 1972). As a result, these observations Ingestion of selected nutrients affects mood and consequently human behavior Came to mind.   Nutrition strategies have been used several times in the past (eg, Williams, 19 59), clear quantitative demonstrations are clearly limited. However, recent clinical days Respond to alcohol, cocaine, and food poisoning. Suggests substantial effects of amino acid precursors and enkephalinase inhibitors (Blum et al., 1988; Halikas et al., 1989). A related study (Blum et al., 1988) No acid supplement (Kantroll^TM) Use of a 30 day cocaine addict inpatient treatment program Investigated in ram. The only difference between the experimental and control groups is that this supplement Was the use of Two main measures were used: leaving the program before completion or Going against physician advice (AMA) and drug starvation. Drug starvation, clear cocaine Related dream phenomena, physical complaints, medication requests, drug-related confrontation responses, program compliance Defenders, upsets and means of violence or threats of neglecting AMA. Amino acid supplement Product groups live significantly better than control groups in both measures. Was. AMA rate is reduced by a factor of 9, and measured drug starvation is significantly reduced did. In addition, staff reported agitation, defocus, and a clear reduction in desire. Was. However, measurements are complex, often qualitative, and subject to many input factors. Depends (Brown et al., 1990).   This study is based on Kantroll^TMBetween clinical experience and basic understanding of neurobiological outcomes in children Search for the part close to the top. Here, the approach is Kantroll^TMUsing To assess the quantitative neurophysiological changes associated with the treatment. Electrophysiology The main part is the event-related potential (ERP) of cognition, evoked by two visual attention tasks Focused) on the P300 component. This electrophysiology for more traditional EEG analysis The advantage of the strategic approach is that it is important to Is to activate any particular system. These cautionary probes probe the ERP component Emerging families, each representing a stage in information processing. However, this specification ERP analysis focused on cognitive ERP, specifically the P300 component. Quantitative ERP changes The range of clinical disorders (eg, attention disorders (Buschbaum et al., 1973; Halliday et al., 1) 976; Richep et al., 1976), schizophrenia (Braverman, 1990), depression (DeFrance et al.). Vasile et al., 1992), dementia (Duffy et al., 1984), and drug use disorders (Br averman et al., 1990, and Braverman and Blum, 1996)) as expected Changes have recently been shown.   The focus of this preliminary report was the attention process. Because partly Changes in attention / or concentration may both precede and accompany persistent drug abuse (Begleiter and Projesz, 1988; Whipple et al., 1988; Parson , 1990), and many mediator substrates that are considered important in attention The Kantroll^TMBecause it is a target for treatment through administration of Another goal of this study Are amino acids that act as precursors or modulators of neurotransmitters The question was whether to affect the nervous system. The study was then normal -Term Kantroll in healthy subjects^TM(Particularly cognitive ERP P300 (Indicated by changes in components), and addressed electrophysiological and performance issues.   Subject. The study included 20 normal volunteer subjects; according to the DSM IV criteria , As determined by a broadly recognized psychiatrist, Has no psychiatric condition. All subjects must have informed consent And each was compensated for their involvement in the study. Each subject will receive a trial As a test-retest paradigm, two series of tests were performed, Acted as a troll. The initial test is performed on day 0 (preliminary test) and then Repeated ~ 30 days later (post-test). Subjects were 6 capsules of Kantroll^TMFrom 28 to Consumed daily for 30 days. The compositions are shown in Table 6. Pre-test or post-test Data from the two subjects was not included due to poor quality Was.   Working tasks. Two operational paradigms are used as probes of electrophysiological research behavior. Used. The first probe was spatially oriented. This is the signal of the first stimulus (Priming cue) appears in different parts of the visual field, a task based on reaction time (Posner et al., 1988). When the first stimulus is available and when it is not available In this case, reaction times were compared for right and left fields. Through reaction time comparison And enable the individual to assess the ability to smoothly switch attention. Instructions on the monitor -Focus on the cross in the center of the screen, and if "*" appears in the box on the right, Press the mouse button and press the left button if "*" appears in the left box. Was that. The box will be replaced with the brightest one. Record the reaction time and ER P was constructed for four categories: (1) facilitating right visual field, (2) right visual field. Non-promoting for visual field, (3) promoting for left visual field, (4) non-promoting for left visual field Progressive. The presentation was random but with the same probability for the four states. Facilitation The box was illuminated for 500 milliseconds prior to presenting the target. Both left and right vision Score and reaction time for each field, and their respective A 'values (standard Signal detection parameters) were recorded. This paradigm is a cognitive process Along with the speed, sample the orientation to the stimulus and the fluidity of attention.   The second probe was an accidental continuous motion. This task is a classic A variant of the theme (Rosvold et al., 1956). Individuals have a specific sequence of characters (for example, For example, if another "T" follows, press the left mouse button for "T"). And was asked to respond. The version of this task stimulates 0.8 seconds With a fixed interval (ISI) of 500 and includes 500 trials. Non- “T” probability set at 50% Alert, the probability of warning "T" is set to 30%, and the probability of target "T" is Set to 20%. The average ERP was built according to one of three states: confusion (A letter other than "T"), a warning signal (the first "T" in the pair), And the target (the second "T" in the pair). In principle, motion measurement is The measurement was the Inconsistency Index (Ringholz, 1989). Previous The frontal cortex appears to be most closely involved in maintaining attention and effort Seem to work well with this type of task (Cohen et al., 1987; Corbe tta et al., 1991), and these tasks are very sensitive to stimulant dosing (Sos tek et al., 1980) is noteworthy.   Recording scheme. The EEG has 28 activity records based on the connected earlobes (A1-A2). Recorded from recording site. The montage uses additional electrodes, front-temporal (FTC1, FTC2), center-parietal (CP1, CP2), temporal-parietal (TCP1, TCP2), and parietal Based on the international 10-20 system, located in the part-occipital (PO1, PO2) area. electrode The impedance was kept below 5 KOhm. Further electrodes are extraocular Used to monitor facts. Vertical eye movement and blinking ( That is, VEOG) passes through electrodes placed just above and below the trajectory of the left eye. Recorded. Horizontal eye movement (i.e., HEOG) is Monitoring was performed using an electrode pair.   EEG and EOG are compatible with 32-channel NeuroScience Brain Imager (0.1-40Hz, 6d B / octave low band, 36dB / octave high band). Unprocessed EEG is SC Under control of AN EP / EEG acquisition and analysis system (NeuroScan, Inc.), 16-bit Sample for 2.56 seconds by analog-to-digital converter (TECMAR Labmaster DMA) I did it. For the construction of the event-related potential (ERP), the average of the waveforms is set at 800 ms intervals It was constructed from a 256-point space. Baseline before stimulation (this is the correction process 100 ms prior to the presentation of the stimulus to establish Started pulling. Single sweep data is baselined by subtracting the average. In corrected. The number of record sweeps varied with the behavioral probe. As a whole 200 sweeps were recorded for spatial placement, and 500 sweeps were accidental Recorded for continuous operation testing. Each segment of the behavior paradigm. Three Parameters, each of which varies with the efficiency of the individual's attention process obtain. These parameters are: ERP component latency, amplitude, and symmetry (spatial Distribution).   Data analysis. First, the T-test statistical map shows all 28 electrode sites (each point Generated in time). This is a statistical probabi from Dufry et al. (1981). It was a variation of lity mapping. Although explorable, this procedure is easy A visualized map is generated, indicating that this electrode site undertakes further analysis. Since P300 is the component of interest, Pz was selected as a site for statistical analysis, This is because the focus of the components seems to be where these visual tasks reside, since they are map-derived. Is a place where Next, the peak latency and peak amplitude (275-325 ms Within the interval). The second stage of the statistical analysis uses a paired T-test model (Statg raphics, 1988), which compares treatment status with baseline. Operation data And analyzed using the same model.   ER from CCPT task superimposed on 28 scalp recording sites for illustration An electrode array scheme using P was made. Correct and eliminate artifacts Vertical external eye movement recording (VEOG) and horizontal external eyeball used for Also includes exercise log (HEOG) records.   Consider first the results from the SOT. Again, this particular paradigm Interesting components (DeFrance et al., 1993) (including N2 negatives occurring within 100-200 ms intervals) Is generated. The N2 component processes negatively, which is the initial stage of the directional response (DeFrance et al., 1993). This component has been found to be enhanced following treatment. But the amplitude change did not pass our pre-established significance threshold [F (1,17) = 2.30, p = 0.0259]. Nevertheless, late in the state before the test Positive (ie, P300 component) in the left [F (1,17) = 8.531, p = 0.0095] and Notable in amplitude for both right [F (1,17) = 16.31, p = 0.009] promoting states Was found larger. Therefore, Kantroll^TMThe average P300 component of the group after administration is It was found to be significantly enhanced when oriented to both right and left visual fields. Was.   Histologic map shows the facilitative (ie, primed) state for the left visual field Was tested for baseline and treatment status. Putter of right view Is not presented because it reflects the pattern of the left field of view. Smell every 100-200ms Thus, N2 negative is shown over the right temporal-parietal region. Again, this ingredient Kantroll^TMEffects approached statistical significance, but larger changes , Related to P300 component, and easily understood by comparing 300-400ms interval Sa Can be Basically, the tissue distribution characteristics of the P300 component remain the same, but the peak Amplitude is Kantroll^TMEnhanced by treatment. Right and left for motion data The reaction time of the mixed nature of the lateral visual field stimulus was earlier at 232 ± 0.03 ms vs. 238 ± 0.03 after treatment. ms [F (1,17) = 8.62, p = 0.001]. In short, border line of N2 component There was a remarkable effect on the P300 component with enhancement. Sensory tasks (CCPT) A remarkable effect was observed in the P300 component related to.   The various components of cognitive ERP associated with accidental continuous motion tasks (CCPT) P300 has many similarities to those generated by successive motion tasks It has component characteristics (eg, DeFrance et al., 1995b; Hillyard et al., 1973). Corrugated Sets were constructed for analysis-confusing, warning signals, and targets- However, only the target waveform needs to be considered. Comparison between preliminary test and post-test , A significant [F (1,16) = 7.422, p = 0.015] enhancement of P300 amplitude was found. Measuring effectiveness To compare average target waveforms at Pz for baseline and treatment status . The potential followed by a large positive (peak around 300 ms) is a classic P300 component You. Again, the target waveform is where the subject responds (by instruction) to the second "T" of the pair. In this case, the waveform was obtained. Kantroll^TMBefore (baseline) and after (process Determining a tissue distribution map between 300-400 ms intervals for the target condition of And the tissue distribution characteristics of the P300 component remain the same. But the amplitude is a preliminary test When comparing the status of the post-test and post-test, enhancement is shown. That is, the baseline and In both and treatment states, the P300 component occupies a central posterior position and As if it were symmetric. Nevertheless, the amplitude of the P300 component Condition was strengthening. Electrophysiological differences exist approximately 4 weeks after treatment However, for the main behaviors that are variable with respect to this behavioral probe (the discrepancy metric) There were no significant differences. The likely reason for this is that these Of subjects were already close to their optimal behavior with regard to their accuracy . However, movement differences can be expected to emerge in the clinical population.   Kantroll^TMA sign of cocaine abuse is altered attention processing Was designed as a potential treatment for cocaine abuse ( Robledo et al., 1993). In addition, human attention processing and cognitive ER The P300 component of P is often linked (eg, Hillyard et al., 1973). next In this regard, it is worth revisiting the neurology of the P300 component. Because this Provides a context for the importance of knowledge. As is widely known, P300 is one of several intrinsic cognitive ERP components whose potential, morphology, and And spatial distribution are highly dependent on the psychological context in which the stimulus is embedded (Sutton et al., 19 65). As a result, the P300 component is due to its putative role in attention and memory And is the subject of much research. Evidence from deep records in humans suggests that frontal lobe structures and In both cases, the anterior (eg, amygdala) and middle temporal (eg, hippocampal) bodies are P300 May be involved in the regulation of components and may actually contribute to its presentation over the temporal region (Halgren and Smith, 1987; Wood et al., 1980). However, the deep temporal structure As considered from earlier studies, it is the only site of production for the P300 component. It does not seem to be. Does temporal lobectomy do annihilate components? (Johnson and Fedio, 1986; Smith et al., 1985). It is so Nevertheless, as in the prefrontal zone (Simon et al., 1977), the deeper temporal lobes Seem to have a distinct regulatory response to minutes (Halgren and Smith, 19 87).   Since the features of any cognitive ERP are highly linked to triggering a behavioral paradigm The behavioral probes used in this study are continuous and selective attention tasks It is important to remember that we have both elements. for that reason, Certain components of ERP (eg, P300) should be relevant in both aspects of attention is there. Interestingly, recent PET studies (Corbetta et al., 1991) show that the orbital frontal cortex Was shown to be closely involved in the selective aspects of attention. Where the attention of persistence Seems to be more limiting of the inner part of the prefrontal cortex (Cohen et al., 1987) , The hemispherical part on the right plays a particularly important role (Pardo et al., 1991; Wilkins et al., 1987). The orbital frontal cortex regulates the activity of the anterior temporal region via hook-shaped bundles So it is surprising that amygdala damage then also affects selective attention There is no. Probably because you can't assign enough emotional values to the stimulus It has been suggested that amygdala damage impairs selective attention (LeDoux, 1993). note Behavior is also known to be affected by the characteristics and disparity of the input information. You. Hippocampus does play this role in the overall selective attention process Wonder Evidence exists (eg, Salzmann et al., 1993; White, 1993). Therefore, The peach body assigns feature values to the stimulus complex, and hippocampus formation compares feature values during stimulation. Orbital frontal cortex-amygdala-hippocampus formation axis, Seems important in the section. Next, within this framework, the P300 Style-independent by-products of later processes (necessary for later emotional, memory, and cognitive processes) Behave as an important basis). Next, the probe for these actions is the forehead-temporal axis. Stimulates the functionality of the pathway along. Forebrain region is involved in cocaine brain response I do.   Attention processing has also been shown to be dependent on biogenic amine regulation (St anzione et al., 1990; Scatton et al., 1982). Precursors for amine synthesis depend on dietary intake. Dietary supplementation can alter the available biogenic amine stores in the brain. And is possible. This may lead to nutritional improvements in brain chemistry for the treatment of certain disorders. Various clinical strategies have been targeted (Blum, l989c). This approach is Utilizes normal cellular control mechanisms, and has psychological outcomes, behavioral behaviors, and And a clear improvement in preventing recurrence. Such nutritional improvements can be linked to these neurotransmission Significant neurotransmission combined with vitamins and minerals central to the synthesis of substances Relies on the administration of the amino acid precursor of the substance. All these chemicals (neurotransmitters, Vitamins and minerals) in active alcohol and drug abuse Not only are they found to be deficient, but often (Blum, l99la).   Second, the study shows that nutritional supplementation increases neurophysiological function in normal controls. And this could be due to the use of amino acid supplementation in the cocaine recovery process. (Blum et al., 1988; Trachtenberg et al.) And Blum, 1988). Future plans, how attention and memory function, cocaine Investigate whether they will be affected in the recovery of abuse. Various neurotransmitters The quality (important for care) depends on the nutrient source for its precursors, Attention deficit and / or rate of recovery may be minimized by selective precursor enhancement unknown. The implications of the reward cascade model are drug use and / or genetic abnormalities Each of these neurotransmitters that can be shown to change functionally as a result of (Blum et al., 1990; Noble et al., 1991a; Noble et al., 1991b; Blum et al., 1991a; Blum Blum et al., 1992; Noble et al., 1992; Blum et al., 1994a; Blum et al., 1994b; um et al., 1995b; Blum et al., 1995a; Noble et al., 1995), facilitate improved brain function. Should be manipulated in such a way to strongly improve feelings, moods and behaviors You. This common disease was first described by Blum et al. (1995a; 1996a) as "reward-deficient symptoms. It is termed the "group", which is a malfunction of the "reward cascade". Of the inventors The result is that treatment of "reward deficiency syndrome" (at least in part) It can be achieved by amino acid loading techniques with zease inhibiting properties.After several years of research, researchers have identified factors that classify alcohol dependence as type A or type B. Can be identified. Recent NIDA-funded studies generally show multiple similar decisions The criteria show that they vary in the classification of cocaine abuse. The consequences are different Be useful in the description of cases and in the design of specific prevention and treatment designs. Can be shown.                                Example 17                   Other polymorphic traits (cholesterol and             MAA technology for low density lipoprotein level)   In our work on the role of various genes in cardiovascular disease, Have four genes associated with cholesterol and low-density lipoprotein metabolism. The offspring were identified. These include serotonin transporter (HTT), oxytocin Receptor (OXYR), dopamine DRD2 receptor (DRD2) and presenilin inheritance (PS1). Each polymorphism is due to a promoter insertion deletion in the HTT gene. (Collier et al., 1996), dinucleotide polymorphisms in the OXYR gene (Mechelini et al., 1995) ), DRD2 gene promoter insertion / deletion polymorphism (Arinami et al., 1997), and P RFLP for the S1 gene (Higuchi et al., 1996). Based on studies of different groups of subjects The scores were as follows: HTT gene 0 = SS, LL, 2 = SL; OXYR gene 278 / 278 = 0, 278/267 = 1, 276/276 = 2; DRD2 11 = 0,12 = 1,22 = 2; and PSI gene 22 = 0,1 2 = 1,11 = 2.   FIG. 8 shows the role of these four genes in cholesterol and LDL metabolism. 2 illustrates the use of the MAA technique in titration.   These results indicate that MAA technology may generalize to any polygenic disorder or trait Prove that. These four genes are responsible for cholesterol and LDL levels. Caused 16.2% and 11.5% of the variance, respectively. The cholesterol p-value is 0.0002 and 0.002 for LDL.                                Example 18   Dopaminergic genes, violence and disruptive / avoidant behavior. "Pathological violence" Regarding, we genotyped 11 adolescents aged 12-19. these The youth is in a boarding action program in San Marcos, Texas, and has DRD2 and D Mutated for both AT1 genes. These subjects consisted of one hour Diagnosed as having impulsive-aggressive violent behavior based on physical interviews. the study Each subject selected for Nicolett^TMMeasured by and widely certified It had a 2.5SD abnormal brain electrical activity map interpreted by a psychiatrist. Of 11 subjects Six of them had the D2A1 allele (56%) and 11 of 11 subjects had DA It carried T1 (VNTR10 allele). The D2A1 allele of the subject Significant association was observed when compared to the control (1/30 or 3.3%) (X2 = 14.9, df = 1, p <0.0001). Similarly, when compared to literature controls, Significant associations were found for 10 alleles of DATI (34/91 or 37.4% , X2 = 7.6, df = 1, p <0.006), not found for 10/10 genotypes (p = 0. 093).   The present invention describes the association between various dopaminergic genes and SAB. SAB For the data set, we found that three dopaminergic genes (DRD2, DA T1, DβH) for outpatients visiting a clinic in Princeton, NJ Genotyping of all 109 subjects and 172 screened controls Similar. Using χ-square, we found that the D2A1 allele was in patients (Millon Clinica l Multi-Axial Inventory Computerized test to compare S2 with D2A2 allele With patients identified as having AB (score> 84) (X2 = 7.6, df = 1, p = 0.006) Was found to be relevant. The D2A1 allele in this study had a mitotic 11 / 22 or 50% and 12/27 or 44% of avoidance subjects A significant association was found when compared to the role (X2 = 16.75, df = 1, p = 0.000044 ). Chi-square analysis uses the approach, SAB, using the DβHB1 allele Did not show a relationship with DAT110 / 10 allele, but In those individuals (18/28 or 68%) diagnosed with SAB, DAT14 Significant associations were found between the 80bp VNTR 10/10 alleles (X2 = 6.3, df = 1., p = 0.012). A similar trend was observed in screened controls (super DβHB1 allele (17/23 or 76%) compared to (but not control) (X2 = 2.9, df = 1, p <0.09). Linear trend analysis was performed for SAB severity. Showed an increasing frequency of D2A1 alleles with increasing (A1 / A1 = 83%; A1 / A2 = 41%; And A2 / A2 = 23%; p = 0.0.005). With multiple changing associations, D2A1 Both progeny and gender were significant predictors of SAB severity. D2A1 confrontation Using the gene, we found an odds rate of 2.79 (p = 0.018) and used gender In this case, it was 3.6 (p = 0.007). Hosmer-Lemeshow goodness-of-fit fit is p = 0.778 The combined contribution to variance was 17.9%. At SAB, DRD2 remains The gene appears to be more important than the DAT1 gene.                                Example 19               Examples of Specific Assays for Gene Polymorphism   The following are used to diagnose a predisposition to RDS, related behaviors and other polygenic traits, It is an example of the specific detection method of various genes proposed in the present invention. Peculiar Many of the dynamic assays are identical to those found in the literature, and are based on MAA technology. The use of such an assay for polymorphisms is illustrated. Those skilled in the art will change And assays to detect specific allelic variants, and And additional genes and assays other than those described herein Recognize that it can be used in MAA technology.   DRD1. The method for examining the DRD1 gene is based on the change from A to G in the 5'UTR. And the PCR described by Cichon et al. (1994).^TMDdel processed by procedure Including the use of polymorphisms.   DRD2. To detect this gene, obtain DNA from the subject and transfer the DNA to TaqI restriction enzyme. Subjecting the DNA fragments to digestion, separating the resulting DNA fragments, Phage hD2G1 (ATCC accession number 61354 and 61355) or specifically binds to the 6.6kb A1 allele of the human dopamine D2 receptor. Hybridizing with that fragment and the human D2 receptor Measuring the presence of the A1 allele of In particular, recombinant phage --Fragments of hD2G1 (ATCC accession numbers 61354 and 61355) are approximately 1.7 kb in size. May be a BamHI fragment having An alternative method for detection is PC R^TMIncludes technology (Noble et al., 1994).   DRD4. DNA is extracted and VENT polymerase and annealed at 70 ° C for 5 minutes. PCR using high denaturation temperature (98 ° C for 1 minute) with a combination of^TM Amplify (Somer et al., 1993). The primers used are (Nanko et al., 1 993), 5'-AGG TGG CAC GTC GCG CCA AGG TGC A-3 '(SEQ ID NO: 23) and D4 = 42 : 5'-TCT GCG GTG GAG TCT GGG GTC GGA G-3 '(SEQ ID NO: 24).   DAT1. Determining the polymorphism of the DAT1 repeat involves VNTR genotyping. Genomic DNA, Extract and PCR DAT1 40-bp VNTR^TMAmplify by The allele at the 3'UTR is PCR using oligomers^TMAnd Pand reported by Vandenbergh et al. (1992a) CR^TMDetermined by conditions. PCR^TMAfter amplification, the product is 8% acrylamide gel And electrophoresed with a set of size markers.   DBH. D'Amato et al. (1989) describe two Taq DβH polymorphisms, named A and B. Reported the existence of. DβH cDNA clone AII (LaLa) containing a 2.7 kb insertion of the EcoRI site mouroux et al., 1987). To improve labeling, the vector is And SalI digestion to generate 5 bands. 3.5 to test for B polymorphism The kb fragment was labeled. Digestion with TaqI restriction endonuclease, agaro Electrophoresis on paper, Southern transfer to nylon filters,³²P-labeled professional Hybridization and autoradiography at 2.8 k The b (B1) and 1.4 kb (B2) fragments are demonstrated.   MA0A. Take advantage of the MAOA VNTR polymorphism (Hinds et al., 1992). This complex polymorphism GT microsatellite immediately adjacent to a novel 23-bp VNTR motif that replicates incompletely Consisting of This polymorphism occurs in both the number of dinucleotide repeats and the number of VNTR repeats. And have different alleles. DNA is extracted by standard methods and then PCR^TMEach primer is labeled with fluorescent HEX or FAM amidite (Applied d Biosystems, Foster City, CA) with primers [<320; 320-333; 334; Be labeled. 2 μl 10-fold diluted PCR^TMThe product is washed with 2.5 μl of deionized formamide. And 0.5 μl ROX500 standard, and denature for 2 min at 92 ° C. d Load on 6% polyacrylamide gel in Biosystems 373 DNA Sequencer I do. The gel is electrophoresed at a constant power of 1100 volts and 30 W for 5 hours. next The gel is scanned with a laser and analyzed using an internal ROX 500 standard. Peak is Genotyper (barge based on fragment size colored by base pair length) 1.1) Recognize in [Applied Biosystems].   PC of mutant region of tryptophan 2,3-dioxygenase gene intron 6 R^TMamplification. PCR to amplify target sequence^TMThe reaction is as follows: 10 mM Tri s HCl, pH 8.3, 50 mM KCl, 1.5 mM, 1.5 mM MgCl_Two, 0.05% Tween 20, 0.05% NP-4 0, 100 μM each dATP, dCTP, dTTP, dGTP, 0.1 μM primer. Primers are: # 11 6 GAC ACT TCT GGA ATT AGT GGA GG (SEQ ID NO: 25) and # 117 GAA GTT AAA T CC ATG TGG CTC (SEQ ID NO: 26). Add the following to make 20 μL: 0.5 U AmpliTaq (P erkin-Elmer, Foster City, CA), 1 μl (250 ng) genomic DNA. Reaction is PE-9600 Therma Recycler (Perkin Elmer) or PTC-100 programmable thermal control Protocol (MJ Research, Inc., Watertown, MA) using the following protocol 5 minutes at 94 ° C, then 30 seconds at 94 ° C for 30 seconds, 60 ° C for 30 seconds, and 72 ° C for 1 minute. Cycle, then 72 ° C for 5 minutes. 10 μl reaction mix to determine if amplification has occurred The solution is electrophoresed on a 1.5% agarose gel in TBF buffer.   PCR above^TMFrom the reaction, 10 μl aliquots were transferred to 1.5 units of restriction enzyme Bs II and final concentration 1x buffer (New England BioLabs, Be (supplied from Verly, MA) and incubated overnight at 55 ° C. To A 10 μl aliquot of the digested product was added to 4% metaphor agarose ( F. M. C. Products, Rockland, ME) 1 hour on gel , 100 VV, 1 × TBE for electrophoresis. Dye gel in ethidium bromide To color. Three size fragments are expected. When the polymorphic site is G / G The DNA was completely digested to yield 673 bp and 359 bp fragments. You. If the polymorphic site is A / A, the 1032 bp fragment is not digested. G The / A heterozygote has three fragments, 1032 bp, 673 bp, and 3 It has 59 bp.   The sequence immediately 3 'of the G → T mutation is GATA. GATC is DpnII system Recognition site for restriction endonuclease. AT just 3 'of G → T mutation The 3 '23 bp oligomer designed to match the C sequence is as follows: (The oligomer is underlined and the two g sites of the mutation are double underlined. );   The mismatch at this third site is determined by PCR^TMMostly its effectiveness as a primer Doesn't hurt.   The 5 'primer was chosen to provide a 29 base pair product. G → T change If the difference is G, the GATC site is truncated and the 22 and 70 bp fragment Generate When the G → T mutation is A, only a 92 bp fragment appears . PCR^TMThe reaction conditions are as follows: 1 μM each primer, 0.2 mM each d. NTP, 50 mM KCl, 10 mM Tris HCl, 1.5 mM MgCl_Two, 0.001% (w / v) gelatin, 2.5 U / 100 μl AmpliTaq® DNA polymerase, 80 ng genomic DNA. PCR^TMThe cycle is 94 ° C for 4 minutes; 94 ° C for 30 seconds, 52 ° C for 90 seconds, 72 ° C for 120 seconds for 30 cycles; 72 ° C for 5 minutes. The conditions for DpnII digestion were 10 μl of PCR.^TMProduct, 0.05 μl 10 U / μl DpnlI; 1.5 μl: 1 M NaCl, 0.5 M Bi s HCl, 0.1M MgCl_Two, 10 mM dithiothreitol, pH 7.9 : 3.5 μl of H_TwoO, 37 ° C overnight. The product is electric with 4% metaphor agarose Run electrophoresis.   HTRIA repeat polymorphism. The method used to determine this complex polymorphism is , Bolos et al. (1993). PCR^TMLabel the product For this, 0.1 μl of each fluorescently labeled primer is used for the reaction. Fluorescent dye , FAM amidite (Applied Biosystems, Foster) City, CA). 2 μl of 10-fold diluted PCR^TMThe product was removed by 2.5 μl Add ion-formamide and 0.5 μl ROX 500 labeled standard, add 9 Denature at 2 ° C. for 2 minutes, Applied Biosystems 373 DNA Load on a 6% polyacrylamide gel in the sequencer. Gel is 110 Electrophorese at 0 volts and a constant power of 30 W for 5 hours. Laser scan Analyze using internal ROX 500 labeled standard. Presence of internal standard for each lane The present allows for very accurate length measurements. The peak is Genotyper (Version 1.1, Applied Biosystems) Then, the size of the base pair length is determined. The computer has two peaks of similar height If a shorter peak is detected, always place the shorter peak in the row of the a allele and The peaks are placed in the row of h alleles. Computer has a single peak Subject is homozygous for the a allele, if concluded that it is conceivable that.   HTR2A gene. HTR2A was described by Williams et al. (1996). It is evaluated to have the listed single base pair polymorphism. Applied Biosy The procedure for using the stems DNA sequencer is as described above.   OB gene. Dinucleotides present on YAC contig containing human Ob gene Ptide repeats have been described by Green et al. (1995): D7S187 3, D7S1875, D7S514, and D7S780. Among them, D7 S1875 is closest to the OB gene. Comings calls this OB1875 That.   Cannapinoid receptor gene. Dawson (1995) Amplify the DNA sample using the primers described below, 5'-GCT GCT T CT GTT AAC CCT GC-3 '(SEQ ID NO: 29) and 5'-TAC ATC TCC GTG TGA TGT TCC- 3 '(SEQ ID NO: 30). This identifies the allele of the (AAT) n triplet repeat I do. PCR using standard methods^TMLabel products and determine resulting polymorphisms (See above).   GABRB3 gene. Described by Mutirangura et al. (1992). Amplify the DNA sample using the following primers: CA chain: 5'-CTC  TTG TTC CTG TTG CTT TCA ATA CAC-3 '(SEQ ID NO: 31) and GT chain: 5'-CAC TG T GCT AGT TTA GAT TCA GCT C-3 ′ (SEQ ID NO: 32). This is 181-201 bp Eleven alleles of the long (CA) n repeat were identified. Use standard method And PCR^TMLabel the product to determine the resulting polymorphism (see above) .   Neuronal nitric oxide synthase gene. The nitric oxide synthase gene is It has been implicated in aggressive behavior in nearby mice (Nelson et al., 1995). The method of Hall et al. (1994) is used. We have studied neuronal nitric oxide Examining the association of dinucleotide repeat polymorphisms in the synthase gene (nNos1a) . Procedures using the Applied Biosystems DNA sequencer As described above.   COMT gene. For the analysis of the COMT gene, the single base pair polymorphism was La chman et al. (1996). This polymorphism is Have been shown to be associated with different levels of gender (Daniels et al., 1995). checking).   Apolipoprotein D gene. DNA was extracted and digested with the restriction enzyme TaqI. Become After agarose gel electrophoresis, a nylon membrane (Hybrid N . Amersham, UK) using standard methods. Hybridize using a 32P-labeled APO-D probe. Two alleles Offspring, 2.2 kb and 2.7 kb were identified.   Human chromosome 2. Microsatellite polymorphism, 2p21 (approximately 7 D2S1788, which maps to 4cM), has been identified (Comuzzie). Et al., 1997). DNA is prepared from lymphocytes and is mapped to MapParis. 6a Linkage Screening Set (Research Ge netics) (169 highly polymorphic micros, spaced approximately 20 cM apart) PCR using fluorescently labeled primers (including satellite markers)^TMfor Used for   UCP-2 gene. This gene contains human chromosome 11 and mouse chromosome 7 Maps to chromosome regions and has been linked to obesity and hyperinsulinemia . The forward primer sequence of this gene is 5'-CAT CTC CTG GGA CGT AGC-3 ' No. 33), and the reverse primer sequence is 5'-AGA GAA GGG AAG GAG GGA  AG-3 '(SEQ ID NO: 34). GenBank accession number for the sequence encoding human UCP2 The number is U76367.                                Example 20                 Example of MAA Technology for Genetic Polymorphism   This example demonstrates a number of polygenic traits independent of psychiatric disorders, A technology can be generalized to all polygenic disorders and all polygenic traits Will be described. The following various examples of different polygenic disorders use MAA technology. And teach how they can be studied. Osteoarthritis   Step 1. Identify the polygenic disorder or polygenic trait to study. Systemic deformability Arthropathy (GOA) is the most common form of joint disease. This is the main cause of disability It is a key cause and one of the top three healthcare issues in developed countries. Place. GOA is present in 10-15% of men and women over the age of 45 and 60 It causes pain and loss of function in up to 70% of men and women older than age. G The etiology of OA is complex and involves environmental and genetic factors. Female twin Offspring studies have estimated that additive genes are responsible for 54% of GOAs (Kap rio et al., 1996). Sporadic GOA is inherited as a polygenic disorder.   Step 2. Adjust the scale to measure the severity of the polygenic disorder. OA Severity is measured based on X-ray using Kellgren score (Kellgren score). gren and Lawrence, 1957).   Step 3. Identify candidate genes to test. OA is involved in cartilage synthesis or degradation. And appears to be due to the presence of thresholds for the number of different genes that play a role. This concept And some of the potential candidate genes are involved in regulating cartilage synthesis and degradation. Is a candidate gene in OA based on the role of.   Step 4. Identification of one or more polymorphisms associated with each gene. The following is about OA Is a listing of some of the polymorphisms that can be used in the MAA technology of the US Pat.   Step 6. Adjustment of dummy polygenes or PG variables. For different candidate genes The score is added to generate a PG score.   Step 7. Perform a univariate regression analysis of PG versus QT or DV. Arbitrary statistics program The univariate regression analysis using Lamb is the first OA (oa) candidate gene (cg) (P G + PGoacg1) is performed on the PG using the score for This is performed using a candidate gene (PG + oacg2). This is "n" O Continue until the A candidate gene is added (PG + oacgn), where n is the additional Is the number of genes.   Step 8. Plot the result. Next, the ADHD score in FIG. A graph is shown to show the result of the gene to be obtained + the gene to be subtracted.   Step 9. The procedure using only the gene to be added is repeated. In FIG. 5, ADHD As shown for genes to add for scoring, only Plot. Cholesterol levels   Step 1. Identify the polygenic disorder or trait to study. Years of research have risen The correlation between blood cholesterol levels and coronary artery disease and stroke Indicated. Genetic factors and diet play a role in cholesterol levels, Identification of the genes involved includes identification of individuals at risk and cholesterol levels. May be important in the development of new drugs that reduce   Step 2. Adjust the scale to measure the severity of the polygenic disorder. Fasting Sample-based blood cholesterol levels provide the best severity scale Offer.   Step 3. Identify candidate genes to test. Directly involved in the cholesterol synthesis pathway Numerous genes have been proposed to play a role in cholesterol metabolism I have. To illustrate the capabilities of the MAA technique, we used cholesterol metabolism. Using MAA technology to assess the role of some genes other than the system itself, Its potential role in regulating cholesterol levels was identified. The present invention They identified four genes involved in cholesterol and lipoprotein metabolism. Specified. These include serotonin transporter (HTT), oxytocin receptor (OXYR), dopamine DRD2 receptor (DED2) and presenilin gene (PS 1) It was a gene.   Step 4. One or more polymorphisms associated with each gene are identified. Each polymorphism Is the insertion and deletion of the promoter in the HTT gene (Collier et al., 1996), Nucleotide polymorphism (Mechelini et al., 1995), DRD2 gene promoter insertion / Deletion polymorphism (Arinaml et al., 1997), and RFLP at the PS1 gene (Higuchi et al., 1996 )Met.   Step 5. Assign scores to genotypes. Based on studies of different groups of subjects, The scores were as follows: HTT gene 0 = SS, LL, 2 = SL; OXYR gene 278/278 = 0 , 278/267 = 1, 276/276 = 2; DRD2 11 = 0,12 = 1,22 = 2; and PSI gene 22 = 0,12 = 1,11 = 2.   Step 6. Adjustment of dummy polygenes or PG variables. For different candidate genes The score is added to generate a PG score.   Step 7. Perform a univariate regression analysis of PG versus QT or DV. Arbitrary statistics program Univariate regression analysis using rams revealed that the first candidate cholesterol (c) gene (P G + ccg1) to the PG using the score for This is performed using a material to which a gene (PG + ccg2) is added. This is all cholesterol Until the candidate gene is added (PG + ccgn).   Step 8. Plot the result. Next, the ADHD score in FIG. Graph the results as shown. FIG. 8 shows that cholesterol and LDL metabolism 4 shows the use of MAA technology in assessing the role of these four genes in   Step 9. The procedure using only the gene to be added is repeated. In FIG. 5, ADHD As shown for genes to add for scoring, only Plot. In this case, all four genes were added. longevity   Step 1. Identify the polygenic disorder or trait to study. Aging is the average year of survival As the age increases and the number of individuals over the age of 65 in the population increases, Is an object of increasing interest. Many genes that can predict how long a person will live Is valuable in identifying individuals at risk of premature death. Specific weight Interventions directed at key gene effects have been extended, as have life itself There can also be considerable benefits in quality of life.   Step 2. Adjust the scale to measure the severity of the polygenic disorder. Aging The natural severity scale for about is its age. However, in this case, The higher the age (the older), the better the phenotype.   Step 3. Identify candidate genes to test. Superoxide dismutase (Yu Certain genes (such as scavengers of free radicals) As such, it has long been known to be involved in animal models of aging, and MAA Technology plays a role in longevity, a large number of previously unsuspected genes There is a possibility to identify a novel gene. Cholesterol levels can affect cardiovascular disease We correlate with major cholesterol levels Two genes that play a role were tested. We also include the APOE gene, Was.   Step 4. One or more polymorphisms associated with each gene are identified. These genes are Was scored in the following manner. The frequency of different genotypes of a candidate gene Comparisons were made across groups of aged subjects by chi-square analysis. The specific genotype is the year If the frequency increases progressively across the age group, this genotype is scored as = 2 Was done. Remaining genotypes depend on relative frequency in those different age subjects And scored as = 0 or = 1.   Step 5. Assign scores to genotypes. Scores for different candidate genes Was added to generate a PG score. Each gene is gradually added to the multigene score Can be   Step 6. Setting of dummy polygene or PG variables. For different candidate genes The score is added to generate a PG score.   Step 7. Perform a univariate regression analysis of PG versus QT or DV. Arbitrary statistics program The univariate regression analysis using Lamb was the first longevity (1) candidate gene (PG + lcg Performed on the PG using the score for 1), then the second candidate gene (PG + Lcg2). This is due to the addition of all longevity candidate genes. (PG + lcgn).   Step 8. Plot the result. Next, the ADHD score in FIG. Graph the results as shown. Plot data about genes versus longevity In cases where the MAA technique is combined with a study of 208 subjects, p = 1.5 × 1 0^-7Three genes giving highly significant results with were identified.   Step 9. The procedure using only the gene to be added is repeated. In FIG. 5, ADHD As shown for genes to add for scoring, only Plot.   MAA technology using any human gene associated with the disorder or trait being studied Only three that could be generalized to any polygenic disorder or trait There is only an embodiment of In the next decade, the Genome Project will conclude Approaching the theory, polymorphisms have been identified in any human and any polygenic disorder It is expected to allow for thorough testing for harm or traits. The present inventors That MAA technology can also be provided for polygenic traits in other animals and plants, And the use of this technology in other species is intended to be encompassed by the present invention. I do.                                Example 21        Anti-craving compositions and from opiates in hardcore addicts   introduction. Over the past decade, narcotic naltrexone (Tr Novel and rapid methods of detoxifying intoxications are available in the United States, Canada, and worldwide. It has sparked interest in many treatment centers throughout many other countries. Was. The drop-out rate among hardcore addicts is still around 9 today Approaching 0 percent. The basic concept in this quick method is to give the patient pure hemp Provides drug antagonists and blocks opiate-induced euphoric effect It is to be. With this approach, most patients do not follow, The habit rate exceeds 99% (S. Hall, San Antonio Me thadone Clinic). The issue of the present inventors is that Block the inducible euphoria (O'Malley et al., 1992; Volp icelli et al., 1992) that drugs have little effect on desire behavior. That is, The present inventors have suggested that amino acid therapy is Both combinations are for hardcore addicts (using euphoric drugs for up to 30 years)   Method. This study is based on the San Antonio Methadone Clini. In c, achieved. The criteria for participating in the study are heroin / opiate Is a hardcore addict if diagnosed using DSMIII Included were both male and female patients considered. Each patient should first be 0.4-0.8 It was pre-evaluated before receiving the mg injection. Evaluate naloxone and its withdrawal (If they were too serious, they were not allowed to participate in this study). Patient Oral doses are administered and then withdrawal symptoms for 1 hour and 1.5 hours. Was evaluated. If the patient passes this test, the patient will receive 50 mg T / day For this study, each patient received a narcotic antagonist according to the above regime In addition, the following amino acids were received daily: DL-phenylalanine (2,70 0 mg), L-tryptophan (450 mg), L-tyrosine (300 mg), L-glutamine (150 mg), chromium (200 mcg as picolinate), And pyridoxal 5-phosphate (30 mg). Days without recurrence, or Tr Was counted. Each patient (with some degree of loss of contact), daily Assessed via human contact. It was dramatic in what it did. Rapid detoxification approach without amino acid therapy San Antonio Metha for over 100 patients The average number of days of drug compliance calculated by done clinic was 37 days. Author Twelve subjects had no recurrence or averaged 262 on combination treatment Days were reported as zero or zero (p at least p <0.05).   Conclusion. The addition of anti-craving prescriptions significantly reduced the desire for opiates, and Is important in helping patients with hardcore opiate addiction while preventing recurrence When matching).                                 Example 22        D2 dopamine receptor messenger as a determinant of reward deficiency syndrome   wrap up. Dopaminergic system and specifically dopamine D_TwoReceptors in the brain Very related to the reward mechanism. D_TwoDopamine receptor dysfunction is an abnormal Quality demanding behaviors (alcohol, drugs, tobacco, and food), and other relevant lines Cause movement (morbid gambling, Tourette's syndrome, and attention deficit hyperactivity disorder) . We have D_TwoVariant of dopamine receptor gene is called "reward deficiency syndrome" We propose that it is an important common genetic determinant.   We have proposed DRD in impulsivity-addiction-obsessive-compulsive disorder_TwoGene A₁Allele prediction Bayes (Rosner, 1986) theorem was used as a mathematical method for obtaining measurements .   Bayes' theorem states that a particular event (deficiency) leads to another event (disease) Likelihood, eg DRD_TwoA₁Allele possession causes abnormal drug and alcohol requirements Widely used in medicine to predict the likelihood of taking action (Table 72).   When assessing screening tests, susceptibility is an individual with the disease in question. Is the likelihood of a positive test; and specificity is disease-free The possibility of a negative test in an individual. For the Bayes theorem, the book We used the following formula:   A hypothesis supporting the data is explained in Blum et al., 1995.   To calculate the specificity, we determined that the alcohol Fully screened for the use of drugs, drugs, and tobacco Used controls were used (Table 71). Previous studies have shown that Did not use strict exclusion criteria for trolls (Blum et al., 1995a) Such efforts are essential. Because alcoholism itself is DRD_TwoGenetic Because it is not a true phenotype associated with typeness (Blum et al., L995b; Neiswagner et al. Comings et al., 1991). In addition, to calculate the sensitivity of genotyping In addition, the present inventors have developed studies in which the proband is characterized for chronic or severe disease. Data were taken from the study (Table 72).   Positive predictive value of the study (PV +) includes both healthy and diseased individuals The percentage of true positive results when testing on a population (Gale n et al., 1975). TaqI A₁If you have a genotype, PV + is 0.744 or 74%. In other words, the positive predictive value was high; however, the PV- 54.8%. The inventors believe that individuals with a related urge-addiction-compulsive behavior In studies excluded from the control group, we expected better negative predictive values. Pooled data for patients with these disorders DRD2 gene variants Shows a strong positive correlation (Yates χ^Two= 68.38, df = 1, P <10^-7).                                 Example 23         Attention Deficit Hyperactivity Disorder Syndrome Assessment Scale (ADHD SAS)   background. Recent literature (past 15 years) indicates that attention deficit disorder and The diagnostic criteria for overactive disorders are very variable. Attention deficit disorder (ADD ) Is still a controversial issue in research on pediatric psychopathology (McGee et al., 1989).   Parents, teachers, children, pediatricians, family practitioners, psychologists, school counselors, etc. Is aware of attention deficit disorder syndrome and hyperactive disorder syndrome in children , And have observed. On the other hand, we explain the phenomenon in North America Have experienced difficulties. Many studies in the literature have shown that hyperactivity and Whether the faults actually exist as a diagnostic condition and whether they Conditions or whether they are independent diagnostic entities Indicates that the clinician continues to have difficulty determining   Attention deficit disorder with overactivity (ADHD) and attention without overactivity Defect failure (ADD) is spreading. It is about 3 to 4 million children and And many adults are suffering.   People with ADHD are suffering from overload; that is, they are In particular, sight, sound and feel are strongly conscious. They are normal in their environment Because they are attacked by the stimulus, they cannot remove the background "noise" and their I can't concentrate on my previous job. They have problems or difficulty concentrating on work . Due to the short notice period, they forget their promises, Forget closing dates and often have legal barriers. Because they have a problem It does not handle the problem when it occurs. Because they are always in a hurry, Have difficulty setting goals or objectives.   People with ADHD tend to be confused. Children's rooms are cluttered; adults Desks are messy; everyday activities tend to be chaotic. For all ages They have difficulty in planning and execute the plan in the usual way Even more difficult to do. People with ADHD have the ability to concentrate Not so, they have difficulty completing what they have started. They complete the job Leave the plan unrealized without being completed. Attic and basement Probably partially filled with sewing work, woodwork, repair, notebook, partially completed The desk drawer contains unfinished letters, summaries, and project summaries. Probably scattered in the picture.   ADHD has nothing to do with intelligence. Many people with this disorder have high intelligence I do. However, they are unable to focus or sustain their interests and There is a tendency. As a result, families, friends, teachers, and colleagues are frustrated. Growl, and think they will fail.   People with ADHD have difficulty adapting to change. Their life is very Full of confusion, even mind small additional changes in their daily work Can be upset. Parents go on a trip, new teachers take classes, family Pets move to new town, pets die-all these changes have ADHD Could create a crisis for   People suffering from ADHD live under severe and severe stress, Cannot tolerate frustration; and when they settle, they often Get angry. Anger came suddenly and explosively, closing doors violently, violently It tends to be a bad word, a temper. Children fight, adults blast anger, and Lose work and keep friends away. Then they regret, but the damage is no longer It has happened.   People with ADHD are frustrated by high levels of frustration. They hate to wait in queue and any kind of delay will excite them . No matter what happens-travel, movies, classes, discussions-they say that And hope to end.   The frustration of people with ADHD makes them impulsive. When they were children, they Run into action without considering the consequences. When they grow up, they drive too fast, Use power tools carelessly and jump into activities without thinking about danger. as a result, he Often hurt themselves or others.   People with ADHD have difficulty in the direction of time and space. They are, It may be necessary to stop and think which is the right hand and which is the left hand; May have difficulty following the instructions of the ream, reading the map, or telling time You.   Many individuals who suffer from ADHD are overactive. As an infant or child, They constantly move, bend, twist, and get into everything. grown up When they are, they are restless, easily bored, and demanded to follow their daily tasks. Become rebellious and move constantly.   Another difference for people with ADHD is that they have abnormal EEG patterns is there. Their beta waves-brain waves related to concentration-are low and their theta waves- Related to relaxation-high, theta waves related to daydreaming and dozing I have been. Therefore, activities related to beta waves, careful prediction and problem solving Is difficult to sustain for individuals with ADHD, There is no. They allow them to stay in theta condition with minimal external stimuli. Prefer activity (Lubar et al., 1991).   When you look at these syndromes together, one picture appears: Too bright, too noisy, too unpleasant, and too quickly Try to adapt to the changing world for comfort.   Early speculation on the cause of ADHD was due to marital disability, lack of parental care, and brain damage , Psychiatric illness, or factors such as alcoholism or substance abuse at home Concentrated. Relevant behaviors included behavioral disorders and antisocial personalities. Later, this Their actions have been shown to be genetically linked to substance abuse disorders (SUD). Recent research Show a significant association between these behavioral disorders, ADHD, and specific genetic abnormalities Have begun to do.   What is the cause or principle of ADHD? . Origins arising from neurotransmitter imbalance It is obsessive-compulsive disorder, a child It occurs in childhood and continues into adulthood. The effect is , Treatment and counseling. Biology about this disorder The theoretical principle has been established by many researchers (Biederman et al., 1992).   Quite simply, the immediate cause is that people with ADHD have a defective file It is a problem with the taring system. In other words, their brainstem reticulum Does not block unrelated stimuli. These people, all sounds, all objects Aware of all the touches, all of them coalesce, chaotic and unbearable noisy It is a place of great confusion. A non-essential stimulus is one that is essential to work or related to others Obtain the same attention as a stimulus.   At a deeper level, ADHD is a communication between brain cells or neurons. Is an issue of communication and probably carries messages between neurons in people with ADHD Involved in neurotransmitters. These brain messengers are in short supply. Outside When the messenger that blocks the next stimulus is lost, too many signals pass through, And create confusion.   At an even deeper level, determine the blueprint for producing neurotransmitters There is a problem with the gene. People with ADHD have at least one defective gene Dopamine (a neurotransmitter involved in the regulation of pleasure emotions and attention) DRD which makes it difficult to respond to_TwoA gene. Other research on genetic abnormalities The ultimate is DRD_FourOther dopaminergic genes such as the receptor gene, dopamine beta Hydroxylase (DβH) gene and dopamine transporter gene in ADHD It has been suggested as a causative factor (Cook et al., 1995; Waldman et al., 1996).   Genetic testing. Due to the genetic complexity of the etiology of ADD and ADHD, we Multi-Plex DNA Based Reward Deficienc y Gene Test) to determine the presence of ADD and / or ADHD. This genetic test measures the presence of polymorphisms in the genetic makeup of the individual being tested. Set. A multiple DNA-based reward-deficient gene test will determine if a polymorphism exists, And which polymorphism, if any, and whether the polymorphism is homozygous or heterozygous Indicates which of The severity of ADHD disorders and symptoms and the identification of the above genes Multiple DNA-based reward-deficient gene tests with an association between alleles Can predict the severity of ADHD symptoms and behavior in an individual.   Multiple DNA-based reward-deficient gene testing is a very valuable tool for treatment professionals. It is a step. Although the deficiencies cannot be rectified at present, they are not disclosed herein as anticraving agents. Compounds that are involved in the production of dopamine in the brain and the level of dopamine receptor activity Clinically proven effective in preventing craving by stimulating Was. In addition, compounds can improve an individual's ability to focus more sensitively. Effective, facilitates the transfer of concentration, increases "at-work" behavior, and It was shown to increase the interval.   Reward Deficiency Syndrome Behavior (ADHD is based on one gene that falls into the category of this syndrome) Measurement) is very highly reliable and effective for RDS On the other hand, differential diagnosis is more difficult. Multiple DNA-based reward-deficient gene testing Significant confirmatory data and a generalized differential diagnosis can be provided; however, we have , University of North Texas Health Sciences Center DNA Identity Laborato ry and the University of Tennessee for a comprehensive (rather early completion) study An overview is currently being created. This is a collaborative rather than a collaborative study possible. Based on the results of this current study, we have made a definitive differential diagnosis. , ADHD (currently the most up-to-date psychometric tests and many diagnostics using interview techniques Is a false positive) reduce false positives in diagnosis, enhance true positives Reducing denial in patients and their families, misdiagnosis (anxiety HD, etc.) and thereby convert incomplete prescriptions to Ritalin Switching, improving treatment planning strategies, and switching between ADD and AH / HD We believe that a true differential diagnosis can be made.   Multiplex DNA-based reward deficiency test kit detects dopaminergic gene deficiency It was operated as follows. The test is 99.9% accurate and non-invasive. The test is Requires the use of buccal swabs; therefore, special training to conduct the test Does not require blood sampling, and the test requires a blood draw (as do other DNA tests) do not do. The swab is then mailed or shipped to a certified DNA lab for processing. Sent by carrier. The present inventors have found that the University of North Texas Health Science s Center DNA Identity Laboratory and the exclusive association for this particular DNA test Have a clerk. Results are processed within 72-96 hours ("stat" evaluation required) If required, time is on the order of 24-48 hours).   Diagnostic and Stati published by AmericanPsychiatric Association In the second edition of the stical Manual of Mental Disorders (DSM-II) (1968), The catastrophic category is “Hyperkinetic Reaction of Childhood )"Met. Diagnostic and Statistical Manual of Men published in 1980 In the third edition of the tal Disorders (DSM-III), this category consists of two separate Discontinuation ("Attention deficit disorder with overactivity" (ADD-H), and " Deficit Disorder ”(ADD)).   Third edition of the revised Diagnostic and Statistical Manual of Mental Disorders The edition (DSM-III-R) was published in 1987. In this edition, American Psychiatri c The Association again chose to combine these two diagnostic categories. I do. The diagnostic category at that time was "Attention Deficit-Overactive Disorder" (ADHD).   Diagnostic and Statictlcal Manual of Mental Disord published in 1994 The current version of ers (DSM-IV) lists three diagnostic formulations: "Attention Deficit / Overactivity" Kinetic disorder, combination type ";" attention deficit / hyperactivity disorder, predominantly careless type "; "Attention deficit / hyperactivity disorder; predominantly hyperactivity-impulsive".   DSM III "Attention deficit disorder with overactivity" and DSM III-R "Attention deficit hyperactivity There is a significant difference in "fitness" between the diagnostic criteria for "kinetic disorder" (Newcorn et al., 1989). Continuous changes in the diagnostic criteria for this condition, and Due to the lack of a significant match between the diagnostic criteria groups, any Diagnostic and Statistical M Built to meet the diagnostic criteria of the edition or revised edition of the anual of Mental Disorders Applicable evaluation stages have limited applicability. This point was made by others, "Diagnost ic Interview Schedule for Children (DISC) ”(Costello, 1983)” and “Di agnostic Intervlew for Children and Adolescents (DICA) '' (Herjanic and Cam pbell, 1977), is based on the DSM-III standard. Cannot be considered appropriate for the selection of subjects in new diagnostic systems. "(Newcor n et al., 1989).   Attention deficit disorder is the most widely diagnosed childhood disorder. On the surface, this state It is rather interesting that the description of the diagnosis of the condition has gone through so many changes; Symptoms are not constant and pronounced in all settings (Bro wn, 1986). Attention deficit-only 20% of boys with overactive disorder He showed ADHD symptoms (Sleator and Ullman, 1981). Often due to overactivity Many boys referred to psychological assessments were quiet in a real test environment. Reported and cooperative by a consulted psychologist (Tobiessen And Karowe, 1969). Attentional c that distinguishes ADD from other disorders orrelate) or the presence of distinctive patterns of cognitive correlation The condition is further confirmed (McGee et al., 1989).   Due to this variability in the presentation of symptoms, ADHD SAS first allows parents, teachers, Or the response from others familiar with boy behavior. Therefore, Individuals who are in the most intense and most frequent contact with the year assess and report boy behavior. In the best position to tell. References (Schachar et al., 1986; Atkins et al., 1985) Reports show child teacher assessments, and adolescent behavior was assessed by clinicians. Highly correlates with personal assessments, neuropsychological assessments, and direct classroom observations .   ADHD SAS shows attention deficit-overactive disorder symptoms exhibited by a boy for a period of time Developed to provide a quick assessment of the level of. This rating scale is overactive A definitive diagnostic tool for use in assessing hyperactive or hyperactive boys Does not mean that Attention deficit-the extent, expression, and limitations of overactive disorder To make an accurate definitive diagnosis, developmental pediatrics, pediatric neurology, clinical psychology, Some specialties, including psychology, speech and language, special education, and occupational therapy Many in-depth test meetings with practitioners in the profession are required. Also, this scale Was not developed to replace close inspection. This type of precision inspection The survey will involve the collaborative efforts of a wide variety of expert practitioners representing the fields listed above. Need power. Therefore, this scale is used for psychological, neurological, It is not a theological, neuropsychological or pediatric evaluation.   Many professionals who work frequently with children and adolescents are quickly implemented and scored. Attention deficit-a schedule that indicates the presence and level of overactive symptoms Need a rule. This need is part of the reported occurrence diagram (incidence fig. ure). This condition occurs in less than 1% of all school children From bottom to over 20% of all school children (August and Garfinkel, 1989). According to DSM IV, the prevalence of attention deficit / hyperactivity disorder is 3% of schoolchildren Estimated to 5%. Limited data on prevalence in adolescents and adults Is done.   In many instances, parents and teachers may be lazy, stubborn, lack of interest, anger, immature Notice the behavior characteristic of attention deficit hyperactivity disorder, which can be interpreted as such. Sometimes , Teachers, counselors, primary care physicians, and healthcare and education Others in ADHD reported that the behavior of ADHD boys was Interpret as the result of discipline. And ADHD boys, those symptoms consistent Worried parents explain the behavior of the boy, But can be interpreted as originating from a parent burdened at the parent's responsibility (because Because children are very quiet and behave well in clinics). If parents or teachers act according to these assumptions or interpretations, they will Exacerbates the response to a boy-based problem. The significant value of ADHD SAS is counselor, For teachers, home, healthcare professionals, pediatricians, neurologists, and other professional practitioners Quick and economical availability, and the attention deficits and / or Or determine the level of hyperactive symptoms quickly and easily. Therefore, professional implementation Can use assumptions or interpretations made by parents or other people for the behavior of the boy. Or deny them.   ADHD SAS is answered and scored in about 15 minutes by either parents or teachers It is a 43 item scale that can be analyzed, analyzed and interpreted. The scale is the parent Or the existence and frequency of behavior, attitudes, or emotions to others familiar with boy behavior Is an objectively scoring method that asks for an answer. The scale is the parent We ask them to respond in an objective manner on the 4-point Likert scale. Scale The choices for files are from “None or almost none” to “Most or always ".   ADHD SAS is an efficient and cost-effective screening device. ADHS S AS is easy to implement and score, and Under supervision, may be used with trained technician or professional assistance. However ADHD SAS does not eliminate the need for a fully skilled clinical boy assessment. This Conscious and unconscious distortions because the format of the evaluation device is a parent reporting format To Especially easy to receive. For this reason and other specific limitations of the method detailed below ADHD SAS is an indicator of the presence and level of attention deficit hyperactivity Should only be used; ADHD SAS should It should not be the method used simply as an original plan. Screenini Device is not a substitute for skilled clinical judgment, but a supplement to it Designed to be.   Individuals with attention deficit disorder with overactivity and attention deficit without overactivity Individuals with impairment can differ in their central attention deficits (Lahey et al., 1985). Both include comprehensive attention length, neglect, difficulty in following instructions, and immaturity Teacher indicates similar attentional deficits as compared to controls Was evaluated. However, attention deficit disorders without overactivity and those studies Attention deficit disorder-hyperactive group, compared to both control groups Distracted, impulsive, respond without thinking, and described as careless . When considering their findings from DeLamater and Lahey, 1983; Cahey 1994, A figure of two somewhat different groups of children with attention problems appears.   ADHD SAS describes both predominant types of attention deficit-hyperactive disorders (August and Garfink el, 1989), and constructed in such a way as to assess the overall level of ADHD disorder symptoms Is done. The results of ADHD SAS include general attention deficit-hyperactivity symptoms (ie ADHD, Combination), presence and quantification level of attention deficit symptoms and hyperactive symptoms To reflect.   If the scale detects attention deficit-overactive disorder symptoms, the results will also Indicates whether the symptom level is minimal, mild, moderate, severe, or extreme .   ADHD SAS is intended for use by parents who describe the behavior of children and adolescents over the age of four Is done. Scales may be used in clinics or in clinical interviews with psychotherapist parents. It is designed to be used during, or during a parent-teacher-counselor talk. There are many settings where this screening method is useful.   But parents are uncooperative, unfriendly, silent, or distorted Turn around or because his or her thoughts are not very organized If the answer does not accurately reflect the parent's understanding, ADHD SAS cannot be used. further , Deletion of 4th grade reading skills (scale reading difficulty is about 4th grade) , A bilingual background on limited English as a second language, Have poor language skills due to neuropsychological deterioration or moderate to severe mental retardation Individuals have difficulty completing the scale.   ADHD SAS is easily implemented by trained professional assistants or technicians and And can be scored. However, final decisions on the use and interpretation of ADHD SAS Confidence should be estimated by experts with advanced clinical training and experience. It is. Anyone who may use ADHD SAS before implementing it should read this manual. Theoretical description of the scale, methods of construction, psychometric properties, and And become familiar with certain limitations. In addition, the user The data includes information about the boy's medical condition, school behavior, and behavior with friends The correctness of scale results in settings used by supplementing Should be trained to make clinical judgments.   May be used to help ensure proper use of ADHD SAS Humans also have trials directed by the American Psychological Association (1994). Be familiar with the standards for the use of and follow or adhere to the testing and evaluation The basic text in the field should be reconfirmed. Attention deficit hyperactivity disorder Users who lack clinical training in the assessment and case management of juveniles with Before using the file, the relevant literature in this area should be reviewed. Attention defect There are some good texts on issues related to boys with overactive disorder ( For example, Rourke, 1985; Rourke, 1989; Rourke et al., 1983; Rourke et al., 1986).   The use of ADHD SAS in both clinical and research settings is based on American Psych professional and ethical guidelines set forth by the Biological Association (1981) You have to follow. For any assessment procedure that focuses on children, ADHD SAS will: Should not be used without informed consent of one of the boy's parents Absent. In addition, users should protect the reliability of results and specialize in using ADHD SAS. Necessary care should be taken to limit use to specific "needs to be known" It is. Communicating the scale results to individual boys or the boy's parents is by identifying the item responses Attention deficits instead of focusing on or reporting on the analysis of The focus should be on the qualitative aspects of overactive disorder. Whenever possible, The individual interpreting the scale results depends on the individual's awareness of attention deficit-hyperactivity disorder and his Or understand and deploy scale results, taking into account her current emotional state You should get parental help when doing this.   Attention deficit-identification of hyperactive disorders depends on clinical sensitivity, as well as neuropsychology and Complex works requiring sufficient knowledge of the clinical and research literature on learning disabilities Business. ADHD SAS is intended only as a screening method. ADHD SAS , Should not be used alone. Other diagnostic methods (eg, pediatric evaluation, pediatric Neurological assessment, EEG assessment, computer-assisted E.E.G., or brain electroactivity mapping Exams, neuropsychological assessments, speech and language assessments, psychiatric assessments) Should be used to supplement, reinforce, and investigate.   ADHD SAS also has many specific limitations to keep in mind when interpreting test results. I do. First, the intent of the scale is not particularly hidden. Therefore, the score Exposure to conscious and unconscious distortions by completed individuals. Second, scale Evaluates the parent's reported assessment of his or her child's behavior at one time.   Attention deficit-Symptoms of overactive disorder are consistent and apparent in all settings. ADHD SAS is therefore not a temporary treatment at the level of ADHD symptoms. May not accurately predict global changes (Brown, 1996).   Implementation of ADHD SAS. All you need to implement ADHD SAS is a pen or pencil And only a rating form. The evaluation form is for one of the boy's parents or Should be completed by both. The assessment sheet is based on the selected socio-demographic factors. Ask to identify information that contains children. 43 test items with instructions and each item Included before and after this sheet with white space to answer.   Ensure demographic information is completely completed at the beginning of the ADHD SAS evaluation form Later, the examiner should give the following instructions: "Here, your children's There are statements that will help me better understand my actions. I tell you each Read each listing and mark each entry as true by marking the appropriate column with an 'X'. I want you to show the period of time. For example, consider the statement "I do not rest on my hands and feet." Please This statement states your child's "none or little" Applies to "sometimes", "significant time", or "almost or always" Do you want ".   As these instructions were spoken aloud, the examiner provided the items and the four answer boxes. Point to each. After the boy's parent responds, the examiner marks the appropriate square with an 'X' And said, "This is the end of the rest of the article. Please let me know. "   Occasionally, the individual taking the exam does not understand the term or concept. Parents can select specific items If there is difficulty in understanding, the examiner will explain the item as unselfishly as possible. Should. For example, if the parent uses the term "the rest and rest of the hands and feet" If he does not understand "restlessness," the examiner says, "This item How often it is difficult for a child to keep his hands and feet stationary I am asking if you think you have it. "   Developing and maintaining unity for individuals completing the scale is very important . From a psychometric point of view, the establishment of sufficient concordance is a conscious distortion of answers, especially parent-child It is essential to minimize the amount of denial of difficulty in offering. Optional by respondents The comment is that the scale is complete, and the scale is his or her child Useful in assessing whether or not it is a quick expression of an individual's interpretation of a given behavior obtain.   ADHD SAS scoring. To score and interpret ADHD SAS, Only evaluation paper is required. To score ADHD SAS, first, ADHD  Each item on the SAS assessment form indicates whether the item measures attention deficit or overactivity. Note that it has the item number along with the code. For example, HO1 is overactive DO4 is the first item to measure attention deficit; ; After about 20% of items,^*" I mean To prevent respondents from getting used to the scoring pattern, Scoring patterns are offset. "^*All items except items marked with "" Eyes are scored in the following manner: responders are "none or few" When marked, "1" is scored, "sometimes" is scored as "2", and " "Great time" is scored as "3" and "Most or always" is Scored "4". "^*Those items marked "" Scored; ie, respondents are marked as "none or few" Then, "4" is scored, "Sometimes" is scored as "3", and " "Time" is scored as "2" and "almost or always" is scored as "1". Is attached. Next, add all of the items coded "D" and add attention deficit disorder Determine the total score for SubScale. Then, "Total attention deficit disorder Put the raw score in the space after the statement "Harm scale raw score".   Add all items coded “H” and add Determine the total score for all. Next, “Total attention hyperactivity disorder scale unprocessed score” In the space after the description, put the raw score. Profile: ADHD symptoms Plot the raw score you recorded, below the level. Raw score By plotting the raw score of your attention deficit symptoms, overactivity Sexual Symptoms and Attention Deficit-Allows the level of overactive symptoms to be read directly Automated transformations exist. In the comments and recommendations section, You will note your impressions and directions about your actions with this particular patient or family. It may be desired to record.   ADHD SAS reasonable and theoretical background. Published and useful Some attention deficit rating scales available are available from the American Psychiatric Assoc Diagnostic and Statistical Manual of Disorders published by iatin It simply incorporated the latest version of the diagnostic criteria. However, this approach is non- The applicability is limited in that it is always time-bound. You will notice As such, only the interpretation of primary symptoms does not change over time, so does the condition exist? No, if the condition is present as attention deficit alone, or There is indeed the question of whether or not it is a defect. If you review the above document, you will notice Thus, the current state of understanding is somewhat changing (fluid). We have: Believe in the legitimacy of construction, and that is the common widespread somewhat predominance of boys I believe it is in a good condition. Here is a preferred method of diagnosing ADHD.   Over the past 30 years, various symptoms and attention deficit-various symptoms of overactive disorder There is considerable debate related to the importance of. Attention deficit-diagnosis of overactive disorder Diagno published and published by the American Psychiatric Association Those who link to the stic and Statistical Manual of Mental Disorders There are some weaknesses due to variability. This is especially true for test builders. apply. Optional Diagnostic and Statlstical Ma according to Newcorn et al., 1989. Built to meet the diagnostic criteria of the edition or revised edition of the nual of Mental Disorders The appraisal scale has limited applicability. Latest Diagnostic and Stati Various evaluation devices based on diagnostic criteria of stical Manual of Mental Disorders With respect to Newcorn et al., 1989, established diagnostic tools (eg, "" Diagnostic In terview Schedule for Children (DIDC) "(Costello, 1983) and" Diagnostic In terview for Children and Adolescents (DICA) "(Herjanic and Campbell, 1977) ) Is based on DSM-III criteria and considers this section in a new diagnostic system. Cannot be taken into account. "   ADHD SAS item selection and legitimacy considerations. Items related to ADHD SAS have been in the last 20 years Derived from the descriptive principles found in expert literature in between. Expert literature After reconfirmation, the principles or principles that describe or explain the basis of attention deficit or hyperactivity Everything that is supported and agreed upon based on theoretical constructs is translated into action statements. Was. For example, the distraction of these boys is universally referred to as a dominant factor. So, "Can you be distracted quickly and easily?" There is an item related to distraction such as "".   Standardization of ADHD SAS. Determining the correlation between ADHD SAS and some other scale Or a teacher or psychologist as a reference by comparison to measure ADHD SAS Or traditional standardization of scale using the judgment of a physician or parent I felt it was necessary. We have a good basis for measuring the legitimacy of ADHD SAS. No sub-measure was found. The scale construction method depends on the scale Measuring operable rules of construction, as published in the Monkey literature In this respect, we justify the scale.   ADHD SAS is designed to measure constructs that fall into the attention deficit provision. S Coring depends on the symptomatic amount demonstrated by the individual and the upper limit of the scale. It is designed to measure the relationship between the total amount available to be demonstrated.   Individuals are rated according to the following scale: Note that the individual measures the scale If the person has less than 40% of the total ability of the intention-deficit symptom, then the interpretation is It does not show any symptoms of dysfunction. " Attentional deficiencies that individuals measure on a scale If it indicates 40-51% of the total ability of symptoms, then the interpretation is "minimal level of attention deficit Symptoms are shown. " The individual measures the total ability of the attention deficit symptoms that the scale measures. If it indicates 52-64%, then the interpretation is "a mild level of attention deficit symptom is indicated ". Individuals show 65-77% of the total ability of scales to measure attention deficit symptoms If so, then the interpretation is "moderate levels of attention deficit are indicated." Individual If the scale indicates 78-90% of the total attention deficit symptoms measured by the scale, the interpretation is " Severe levels of attention deficit symptoms are indicated. " Individual measures the scale If it indicates 91-100% of the total ability of attention deficit symptoms, then the interpretation is "extreme levels Attention deficit symptoms are shown. "   Individuals are also rated according to the following scale. The individual measures the scale If the person has less than 40 percent of the total capacity of the overactive disorder symptoms, then the interpretation is "No overactive disorders are indicated." The individual has an overactive disorder measured by the scale If it indicates 40-51% of the total ability of the harm symptom, then the interpretation is "minimal symptom hyperactivity A failure is indicated. " Individuals measure total performance of overactive disorder symptoms as measured by the scale If it indicates 52-64% of the force, the interpretation is "indicating mild overactive disorder" You. If the individual shows 65-77% of the total capacity for overactive disorder symptoms as measured by the scale If so, the interpretation is "indicating moderate symptomatic hyperactivity disorder". Individual, scale If it indicates 78-90% of the total capacity of the overactive disorder symptoms as measured, the interpretation is "severe symptoms Is shown. " The individual has an overactive disorder measured by the scale If 91-100% of the total ability of the harm symptom is indicated, the interpretation is "extreme symptomatic hyperactivity disorder Is shown. "   Individuals are ultimately rated according to the following scale: Individuals measure the scale Attention deficit-if it has less than 40% of the total capacity of the overactive disorder symptoms, The interpretation is "Attention deficit-no overactive disorder symptoms are indicated". Individual, scale If they indicate 40-51% of the total ability of attention deficit-overactive disorder symptoms to be measured, the interpretation is "Minimal overactive disorder symptoms are shown." Note that the individual measures the scale Willingness-If 52-64% of the total capacity of overactive disorder symptoms is present, the interpretation is "moderate hyperactivity. Dyskinetic symptoms are shown. " Attention Deficit Measured by Scale-Overactivity If it indicates 65-77% of the total capacity of the motor disorder symptoms, the interpretation is "moderate hyperactive disorder symptoms Is shown. " Attention Deficit Measured by Scale-Symptoms of Overactive Disorder The interpretation is "severe hyperactive disorder symptoms" if it indicates 78-90% of the total ability of It is. The individual measures 91% of the total ability of attention deficit-overactive disorder symptoms measured by the scale. If it indicates 100100%, the interpretation is “indicating extreme hyperactive disorder symptoms”. Attention Deficit-Interpretation and Clinical Use of the Overactive Disorder Symptom Rating Scale Interpreting ADHDSAS results Case study                                 Example 24 Trinucleotide (GGC) repeat polymorphism of the androgen receptor gene (AR),       Association of ADHD, behavior and rebellious behavior disorders in Tourette syndrome   Many, including ADHD, CD, ODD, antisocial personality disorders, reading disorders and other harmony disorders Behavioral and cognitive impairment and autism are 3-5 More than twice as common (DSM-IV, 1994). Hormonal and environmental factors , But may include genetic factors. Specific gene Is most easily understood if the gene is X-linked. Therefore Depends on the frequency of related alleles and the percentage of variance attributed to the gene And assuming a dominant recessive form of inheritance, X-linked genes are May be part of the excess. Genes are also important for response to testosterone Is very well suited to play a role in the male / female ratio. The androgen receptor gene (AR) is such a gene. This is X staining Located at Xqll-12 in the body (Migeon et al., 1981; Brown et al., 1989).   We consider the shorter of the normal alleles of the ARCAG and GGC repeats (this It is sensitive to increased levels of androgen receptor and testosterone. One or more childhood disruptive behavior disorders, especially behavioral disorders and rebellion Can be associated with sexual behavior disorders and explain some of the male predominance in these disorders Hypothesis that To test this, the present inventors Series of 326 individuals consisting of 267 and 59 controls with Sut syndrome In the body, GGC (Sledden et al., 1992, 1993), a mutation in exon 1 of the AR gene The nucleotide repeat polymorphism was tested. Dopamine (Valzelli, 1981) and cello Tonin (Brown et al., 1982; Lindberg et al., 1984; van Praag, 1991; Coccaro, 1989). ) And aggressive behavior are frequently associated with the AR gene for behavioral disorders and ODD. Impact dopamine d_TwoReceptor gene (DRD2) and serotonin transporter gene (H TT). In this experiment, the human androgen receptor gene (AR) was Shorter alleles of GGC trinucleotide repeat polymorphism may lead to behavior disorder (CD) Is it related to symptoms of sexual behavior disorder (ODD) or attention deficit hyperactivity disorder (ADHD)? Went to determine if.   Method. Allele frequencies were determined for 267 individuals with Tourette syndrome and 59 326 subjects (237 males and 89 females, all non- Ten American whites). About shorter alleles in men Hemizygosity, or homozygosity for shorter alleles in women Eight quantitative behavioral measures tested simultaneously by MANOVA for correlation with gender presence did. Linear regression analysis was used to determine the percentage of variance due to the AR gene. This The dopamine D2 receptor gene (DRD2 ) And the percentage of variance due to the serotonin transporter gene (HTT).   Subjects tested had 59 controls and 267 Tourette's syndrome It consisted of individuals who had. Subjects and controls and behavioral assessment Details are provided herein. In these experiments, we have: Tested the quantitative properties of: inattention, impulses, hyperactivity, CD, ODD, learning disabilities (LD) And academic performance at primary school (GSAP). In one of the current and comparative studies, We have added a quantitative tic score (Comings et al., 1996).   The GGC repeat polymorphism of the AR gene was determined by the technique of Sleddens et al., 1992, 1993. Amplified by the lase chain reaction. Irvine et al., 1995 state that 16 repeats are most common (0.57 ), Followed by 17 repeats (0.32) and 15 repeats (0.08) Was found. The only other allele was 10 repeats. AR alleles and personal identification For analysis of possible correlations with quantitative behavioral scores, the AR genes were: Scored for:> 16 repeats = 0 for men, ≧ 16 repeats = 1; for women:> 16 // 16 repeats = 0; heterozygotes = 0; ≧ 16 / ≧ 16 repeats = 1.   Dopamine D_TwoUsing the TaqIA polymorphism of the gene (DRD2) (Grandy et al., 1989), The role of this locus compared with the AR gene in disability was assessed. This polymorphism Based on evidence of positive heterosis in sex (Comings and MacMurray, 1998), It was scored as 11,22 = 0 and 12 = 1.   Using insertion / deletion polymorphisms in the promoter region of the serotonin transporter gene (Hells et al., 1995, 1996). The HTT gene was set as SS = 0 and SL, LL = 1. Cored (Kauck et al., 1997; Lesch et al., 1996).   Frequency of AR allele or alleles in TS subjects versus controls Were tested by Chi-square analysis. The need for Bonferroni correction To avoid, eight behavioral scores were examined simultaneously using MANOVA. Three To test for additive effects of the genes, an AR + DRD2 + HTT score was generated. Here Different gene scores were added for each individual. This means that 0 (of 3 genes) Genotype not related to any of them) to 3 (genotypes related to all three genes) Girth was given. AR, DRD2 and HTT genes alone or in combination Using linear regression analysis, the percentage variance of the described CD, ODD and ADHD scores Were determined. The hypothesis that these three genes are additive in their effects To test the hypothesis, average the linear ANOVA for each score (including all ADHD scores) Tested.   result. The frequency of the AR allele was determined. Different among the 59 controls The frequencies of the repeated alleles are as follows: 10-0.01, 12-0.09, 15-0.03, 16-0. 47, 17-0.36, 18-0.01, 19-0.01, 20-0.01. Compared to frequency in TS subjects Allele frequencies in the control were determined. All the alleles, Chi-square between control and TS subjects = 19.69, d.f. = 11, p = 0.0731. Repeated conflict In our study of a potential correlation between gene length and phenotypic effects Thus, we have found that the most procedural approach is to combine alleles with short groups. Split into long groups and make the two groups as equal as possible That is, I found out. According to this approach, we have developed AR Alleles were split into those with more than 16 repeats and those with less than 16 repeats. Control Compared to (0.60), TS subjects had> 16 allele (0.66) frequency and increased There was an insignificant tendency (_λ2 = 1.06, d.f. = 1, p = 30). Therefore, Difference at α = 0.05 exists when comparing between control and TS subjects do not do.   Table 1 shows the results of MANOVA classified in the order of decreasing significance. CD score is the most ODD score was significant (p = 0.022) and significant (p = 0.005) Sex scores were also significant (p = 0.032). Tic, GSAP and LD scores Least significant (p> 0.6). Only men have a preferential link to this CD To investigate the question of whether or not there is Were compared with the results in women (n = 89). Checks due to smaller numbers Due to the loss of output, neither trait (wait) is significant for any gender Did not. However, when classified by p-value, CDs for both genders Was most significant.   Because of the potential association between AR variants and sexual behavior, we In a subset of subjects, between the AR gene and the sexual behavior score (Comings, 1994) A post hoc analysis of possible relevance was performed. This was not significant. Post-mortem analysis To determine whether the effect of the shorter allele is recessive or dominant Went to women. For all scores, the mean for heterozygotes is Consistently similar or less than> 16 /> 16 homozygotes, this Indicates that the effect of the ≧ 16 repeat allele is recessive for that effect, and ≧ 16 / It shows that only ≧ 16 homozygotes show the effect.   Table 74 shows the results of the regression analysis. For CD score, AR gene is 2.4% of variance (P = 0.005). By comparison, the DRD2 gene accounts for 1.3% (p = 0.041 ), And the HTT gene accounted for 0.5%. Combined AR and DRD2 genes are dispersed Accounted for 3.3% (p = .0009). This increases to 3.5% when the HTT gene is added (P = 0.0007). The AR gene accounted for 1.6% of the variance in the ODD score (p = 0.022 ). Here, AR and DRD2 genes are more compared to DRD2 genes, which account for 1.4% of the variance Yes, and the HTT gene accounted for 0.7%. All three genes are worth the ODD score It accounted for 3.2% of the scatter (p = 0.001). The AR gene accounts for 1.1% of the variance in the ADHD score (P = 0.053). All three genes accounted for 2.7% of the variance (p = 0.0027).   The linear ANOVA results of the additive AR + DRD2 + HTT score were tested by linear ANOVA, Determine if there is a gradual increase in scores in subjects with an increase in the number of related genotypes. Specified. Inattention, impulsivity, hyperactivity, ADHD, ODD and CD scores were all at α = 0.05 Was significant. In Bonferroni corrected a of 0.05 / 6 or 0.0083, hyperactivity, Impulse, ADHD, ODD and CD scores were still significant.   By MANOVA, the presence of the short GGC allele of the AR gene, CD (p = 0.005), There was a significant association between ODD (p = 0.022) and hyperactive (p = 0.023) symptoms Were present. Association of these alleles is highest for CD in both men and women It's gone. The AR gene accounted for 2.4% of the variance in the CD score. AR, DRD2 and HTT inheritance The combination of offspring was 3.5% of the variance of the behavioral disorder score (p = 0.0007), It accounted for 3.2% (p = 0.001) and 2.7% of the variance of the ADHD score (p = 0.0027).                                 Example 25               Effects of chromium picolinate supplementation on body composition:                 Randomized double-masked placebo control study   Introduction: We have also tried to answer some methodological questions. First Or supplementing CrP affects caloric intake through its appetite impact or Increase caloric expenditure, and via increased metabolic or daily activity levels I wonder? Second, caloric intake between experimental or control groups Control the difference in energy and / or energy consumption by the inventors, and Would a similar result be achieved if excluded from the calculation? Third, other than body composition Measuring instruments (eg, dual energy X-ray absorptiometer (DEXA)) Even more accurate, and is less dependent on the subject's ability to perform the test. Is the result repeated using (no))? Fourth, other studies (Anderson, 1995) High dropout rate (29.7%) found in Despite the similarity of the three study groups for line measurements, selective friction Do you bias your knowledge by rubbing? When methods to reduce file loss are used , Or these similar results when "intent to process" statistical analysis is used Will it occur?   In order to answer these questions, we found that in physical activity and calorie intake, Use the DEXA test for body composition, using measurements to control Use a method to achieve almost perfect compliance as the final exam is completed. Was.   Materials and methods. All 130 patients were enrolled in the study and 122 (93.8%) ( 17 men and 105 women with an average age of 42.3 years) completed all final measurements . Patients are offered at various fitness clubs in San Antonio and Houston, Texas And fitness instructors and sales staff from and athletic clubs (They are members of the club (they have joined or recruited friends, Provided information about the experiment to one of the participant's relatives)) did. In most cases, the fitness instructor will provide Receive rewards by monitoring subjects as they progress Report physical activity levels and caloric intake in follow-up data, and To complete the trial. All subjects should be given informed consent Before asking her to consult her doctor.   Numerous experiments have also shown that DEXA has been shown to reduce fat and lean mass in meat samples and animal carcasses. That the content can be determined accurately (Evans, 1989; Evans and Meyer, 1992; Evans, 199) 3; McCarty, 1993), and less than 1% whole body bone mineral content with typical precision error The actual skeletal mass and total body calcium and non- It shows that they are always correlated (Felig, 1975). In obese patients or obesity Has been found to be an accurate method of assessing body composition in non-patients (Page et al., 1993; Eckel, 1992). First experiment based on DEXA accuracy reported in 1990 (Mooney and Cromwell, 1993) and three subsequent experiments (Page et al., 1). 993; Hasten et al., 1994; Evans, 1989). These are DEXA underwater Correlate with gravimetric determination, heavy water dilution and whole body potassium (Page et al., 1992), but with DEXA Error in the measurement is less than half the error obtained using whole-body or underwater tests. Suggest that there is. Specifically, the variance coefficient for Lunar Corporation's DEXA (CV%) is reported as follows: fat mass = 500 g +^-2.5g; FFM = 600g +^- 1.3 g; and total tissue mass = 400 g +^-0.6g. Used to evaluate various clinical disorders (Lindemann et al., 1993), the reliability of DEXA is relatively short Monitoring the effects of restriction and / or exercise on local and systemic composition (Page et al., 1993; Eckel, 1992). Recent total of studies on DEXA The theory goes to one critic that DEXA is the most critically analyzed of what is currently available. It was concluded that this was a body composition device.   DEXA offers a three-compartment model of body composition: fat, lean body mass And bone mineral content. The measurement is stable, with an effective energy of 40 and 70 keV 78kVp to achieve a congruent beam of a dual energy beam And a K-edge filter (cerium). Equipment (un it) performs a series of transverse scan moves from head to toe at 1 cm intervals; scan The area is about 60cm x 200cm. Approximately 120 pixel elements per traverse Collected (each pixel is approximately 5 × 10 minutes). 16cm / sec scan for whole body measurement 10-20 minutes at speed or 20 minutes at 8 cm / s scan speed You. R value (ratio of low energy decay to high energy decay in soft tissue) is 1.2-1 .4 (Lindemann et al., 1993).   Changes in scale weight, body fat%, fat mass and FFM In addition to comparisons, we also made our previous experiments (Glinsman n and Mertz, 1966). BCI is A decrease in body fat and an increase in FFM are positive treatment results, while fat mass Based on the hypothesis that an increase and a decrease in FFM are negative treatment outcomes. Hence the fat A decrease in fat mass and / or an increase in FFM is scored as positive, Increase and / or decrease in FFM is scored as negative, and BCI is The net result was a combination of these scores. Scale body as a measure of change BCI's superiority over weight is part of the exorcise program In studies examining changes in body composition during life (Liarn et al., 1993), as well as behavior Does it involve a behavior modification program (Hasten et al., 1994) Proven in patients receiving or without medication. Placebo glue Comparison between two groups in a group using a two-tailed Student's T test , Assuming equal variance, and in the experimental group, caloric intake and Analyzes of co-variance to make groups equal in consumption Performed using   Signing informed consent forms and reducing the dropout rate Both were asked to provide the patient with a 100 ＄ check. The patient has a final DEXA study If the final questionnaire for the experiment and the experiment cannot be completed, the check will not be discarded. Was. No matter how good or bad the patient adheres to the investigation protocol They frankly report how well or not following As long as you have completed these checks, you will only be able to return these checks once you have completed the final exam. Advised the patient to be conditional. After completing the initial DEXA study, patients Provide a report of their test results, and randomly assign numbers from 1 to 130 Was. This is either 400 μg of chromium picolinate or an inert placebo (these are apparently Correspond to bottles containing capsules having Investigators can also divide products. Distribute For both research technicians and patients, which patient number corresponds to placebo or active product I didn't know if An independent local pharmacist works as a custody for the experiment , And the bottles were randomly assigned subject numbers. Bottles can be “X” or “Y” Pre-labeled with any of the active products or placebo Corresponding to one of the goods. At the completion of the experiment and when all data has been collected and When pewter analyzed, the custodian opened the cover provided by the manufacturer. To indicate which products are active, and then notify the senior investigator (GRK) Was. All information is transferred to the University of the Analyzed at the Texas Health Science Center under the direction of the second author (KB). Trial At the end of the study period, patients who have completed the final Providing checked checks and cross-checking of used products As to report how many capsules you actually consumed each day Begged. Subsequent analysis of these data indicated that the average active subject was 357 μg / day Of CrP was consumed.   General procedures for assessing calorie intake, nutritional information for general foods, and daily calories -Provide patients with a workbook outlining a diary on calculating and recording balance Provided. To monitor and regulate differences in energy expenditure due to physical activity, Throughout the waking hours, all patients had previous studies (Evans and Press, 1989; The pedometer used in Kitchalog et al., 1993, which shows their pedometers during each day The number of steps, or the number of step equivalents in the activity, where attaching this device is impractical Do). Patients recorded the total number of steps taken each day and recorded their caloric intake. Recorded in the same diary used for Following this, + or^-3,500 Using the formula to change Lolly to 1 pound of body fat, the patient's net Used to adjust for changes.   result. Table 75 shows the baseline descriptive statistics for 122 patients who completed the experiment I will provide a. Any comparison between patients who did not complete the experiment and those who completed the experiment Showed that there were no significant differences in body composition parameters.  Table 76 provides a comparison of the changes that occurred during the 90 day test period.   Consideration. A summary of the baseline data in Table 76 shows the body composition parameters. Indicates no statistically significant difference between the two groups in the deviation You. This is a randomization process when providing two equivalent groups of patients. Indicate that the process is well done. The data in Table 77 is in calories Equalize groups using corrections for intake and energy expenditure CrP supplementation is very significant in scale weight,% body fat and BCI It has a significant effect. There is no correction for calorie intake and consumption. Even so, changes in the active group have been Consistent with the observed changes, including a significant decrease in body fat (p = 0.02) That is worth noting.   The main improvement in body composition in this study was reduced body fat. Worthy of note. The DEXA test is one of the few techniques for measuring body composition This provides a direct physical measurement of adipose tissue. With many other measurements of body composition Similarly, hydrostatic testing is all about some cadaver experiments Hypothesis that the patient's body density reflects the same proportion of fat, as found in The theory relies on the evaluation of the patient's body fat. In addition, even with static pressure testing, the patient's body density can be measured. Does not actually measure body volume for calculations (this is when entering and exiting water). Estimated from the scale weight obtained when Therefore, using static pressure gravimetry Even though the patient's body fat is not derived from physical measurements of adipose tissue, Derived from the evaluation. And, of course, the assessment from static pressure testing Subjects may be consistently affected by their ability to exhale, as well as Can be affected by the dispersal of lung volume over time, even when You. The DEXA test solves these difficulties. Because, to get a measurement, Rest on open test table for 15-20 minutes while body is being scanned Only that is needed. Generates relatively small changes in body composition Avoid controlling the variability of test techniques when attempting to measure product efficacy. If not, it seems to the present inventors.   The requirement to provide a conditionally refundable deposit to the patient is to complete the final test. It appears to have made a dramatic difference in the number of subjects completing. by this Need to use statistical controls such as 'intention to treatment' Is determined. Post-experimental critiques are processed by the subject as a reasonable request. Not looking at the requirements to provide a deposit, he said. Replenished in this experiment Of the 130 subjects, only 8 failed to complete the final test. One person Subjects became pregnant and were asked to withdraw from this experiment. Three other Specimens moved from the area and one fell ill during post-testing , And the three did not explain. Therefore, since all have a will and a purpose, There is no dropout from the experiment, and this cannot bias the results. Our data is not Not constant, but deposit requirements have some value for further experimentation It seems.   The requirement to provide a conditionally refundable deposit to the patient depends on the subject Is completely based on completing the experiment and the final questionnaire of the experiment, and How well or how well the patient follows the protocol It didn't matter. Take the product in placebo and active groups Equal number of patients who failed, of course, matched results across groups Do not let. Placebo patients who fail to take the product do not affect the outcome measure. What This is because placebo contains no active ingredients. But active glu Failure to take the product in the soup weakens the effects that the active product can have. In fact, active patients who are not completely compliant are effectively placebo patients. Therefore, Lack of compliance reduces the difference between the two groups by its very nature. At the very least, this is based on the exact amount of product consumed by the subject. Stress the need to obtain data. Weekly check-in and use of personal monitoring Provides the inventor with more comprehensive data, and reduces the mountain of bias, And lack of compliance could have on top of the resulting measurements.   Conclusion. These data are based on the Body Composition Index (which is The sum of the net increase in non-fat mass added to the sum of the net decrease in body fat Chromium picolinate supplementation is used when the body composition Indicate that significant improvements can be achieved in                                 Example 26                Polygenic inheritance and micro / mini-satellite   Micro / minisatellite polymorphisms in psychiatric inheritance. Mini satellite 6 It is defined as a repetitive sequence up to 5 base pairs in length (Wright, 1994). Microsa Terite consists of shorter repeats, variously defined as 2-5 bp in length. This implementation For purposes of example, unless described in detail, the invention is intended to cover both. Use the term, micro / mini satellite.   Due to the high frequency of micro / minisatellite repeats throughout the genome, The inventors and other researchers frequently use these polymorphisms in related studies did. Our initial assumptions are the same as neutral or silent single base pair polymorphisms. Similarly, micro / mini-satellite alleles are other “interactions” that affect gene function. It was in linkage disequilibrium with the "worldly" mutation. But, After several years of studying these polymorphisms, we have found that micro / mini-satellite He began to suspect that the body could be a "critical" mutation. The inventor believes that extremely long trips Although these studies did not include Rett-repetitive polygenic inheritance, these studies are sufficiently Even if they are within the range, changing the length of the repeated allele Introduce the concept that gene functions can be affected through various functions. Related Two aspects of these micro / mini-satellite polymorphisms (their mutation rate and Their size).   The mutation rate of micro / mini satellite alleles is higher than that of non-repeated sequences. High (Jeffreys et al., 1987). Lack of exchange of adjacent markers indicates that new mutations do not replicate (Slippage) or a complex conversion-like event ( Wolff et al., 1989). The high mutation rate indicates that these polymorphisms are Benefits can be made lower. This is because linkage disequilibrium (This requires that two different polymorphisms remain in phase for many generations. Because there is too much noise introduced is there. However, micro / mini-satellite mutations are themselves "critical" If they are alleles, regardless of the high mutation rate, they are actually More powerful about   Linkage disequilibrium links micro / minisatellite alleles to specific phenotypes When involved, each time a new mutation occurs in the satellite, a "critical" allele There are certain opportunities that have occurred on the same chromosome as the offspring. But on average Therefore, shorter mutant alleles are associated with longer mutant alleles. There is no tendency to be in linkage disequilibrium preferentially with "border" alleles. Only And if the size of the repeat plays a role in gene regulation (see below), Characteristic is different from the size of a particular individual allele or allele sequence. There should be a tendency associated with a group of alleles of the sickle. Repeated gene frequency If a major peak is present, both shorter and longer alleles May be associated with a phenotypic effect.   Both length and sequence can be related and different sizes of micro / mini satellites The possibility exists that light alleles may have an effect on gene function. this The hypothesis is that different micro / mini-satellite alleles are Is very more likely if it can be shown to have an effect on fact, There are many examples of this.   General hypothesis of polygenic inheritance. Micro / mini-satellite hypothesis of multigene inheritance Various aspects are as follows: multiple micro / mini satellites are involved Effective on gene expression; many genes have more than one micro / mini satellite As a result, many genes are functional allelic variants Exists in a range. Genes associated with some micro / mini-satellite polymorphisms Are present with multiple alleles, especially with multiple functional haplotypes. Exist. Most genes are associated with ± 10-15% of the average level of gene activity At the same time, the range can be as high as ± 40% and multiple micro / mini satellites If site polymorphisms are involved, their effects may be additive.   In addition, significantly functional variants range from 1% to 100% of the disease The rate is general. Hyperactive alleles (> 10% of mean) and hypofunctional alterations Where there is a binomial distribution of alleles composed entirely of bodies (<10% of the mean) If so, 100% morbidity can occur. Individually, these functional variants are phenotypically It has only a modest effect (0.5-8% of the variance) and rarely causes disease. You That is, these are, in general, classical monogeneic disease autosomal dominant or inferior. Not the cause of sexual disorders. Most micro / mini satellite polymorphisms are exons Mutations in polygenic disorders are usually outside the exons because they are not And often outside of the transcribed sequence. More than 6 genes have a given disorder Log score linkage study loses power when related to harm (Risch and Merikaangas, 1996; Weeks and Lathrop, 1995). Linkage studies The presence of a given allele is related to the presence of the disorder, and the absence of the allele is Based on the assumption that it is related to the absence of a fault. In contrast, in polygenic inheritance Disorders are associated with the presence of a threshold number of alleles of various different genes. like this In addition, many members of a family can carry a given mutant gene, but have an essential threshold number. Since no other mutant genes are present, the disorder may not be present. Therefore, Many members of a family may have a particular gene and may not have a disorder And other members of this family with a disorder do not carry the mutant allele. May be (Comings, 1996f, l, m).   Both hyperactive and hypofunctional alleles can have an effect on their phenotype. For example, certain receptors leading to receptor hypersensitivity in psychiatric inheritance Receptor inheritance leading to an increase in gene expression or decreased receptor sensitivity Both reductions in offspring expression may be associated with an altered phenotype. Polygenic disorder Means that an individual has a threshold number of dysfunctional or hyperactive genes that affect the same phenotype. It occurs when inherited. Thus, 20 different polygenes play a role in certain quantitative variables. If so, no one has more than 10 of these impaired or hyperactive variants. Present the phenotype that has been changed. Threshold number indicates allelic decline or hyperfunction And the severity of the altered phenotype is polygenic It depends on the degree to which the number exceeds the critical threshold number.   Micro / mini-satellite is so common that it can cause polygenic disorders Is relatively high. Therefore, polygenic disorders are much more common than monogenic disorders . For frequencies of large multigene general populations ranging from 25% to over 50%, threshold numbers remain. Biography Opportunities are much higher than for monogenic disorders. Predetermined micro / mini For satellite, allele depends on genetic background of other genes Can have a positive or negative impact on the phenotype and the nature of the phenotype. Examples are Between Cain-Induced Delusions and Nine Alleles of the Dopamine Transporter Gene (DAT1) Is an observation by Gelernter et al. (1994) on the association. In contrast, Cook et al. (1995) and Comings et al. (1996j) show 10 alleles of the DAT1 gene and attention deficits. An association between hyperactivity disorder was observed. From these different reports, one-sided Can conclude that the other observation must be wrong. But both are correct The reasonable possibilities and the different micro / mini-satellite There is a reasonable possibility that alleles can be associated with different phenotypes You. A sensible approach to studying polygenic disorders selects candidate genes And the closest micro / mini-satellite polymorphism for the appropriate quantitative trait To investigate the effects of alleles.   The above proposed characterization of polygenic inheritance has a number of further implications. Many micro / mini-satellite polymorphisms cause transcription or translation of the most proximal gene And the possibility of changing the proportion of When it comes to micro / mini-satellite, many and the largest genes possible Have the potential to contribute to the polygenic inheritance of the phenotypes they control to some extent.   On the potential role of certain genes in psychiatric disorders or other disorders Many studies begin with a search for mutations in exons of candidate genes. This If such studies are negative, the gene may not be related to the disorder being tested. It is concluded. Polygenic traits are non-exonic if most of the mutations are involved in a complex way And such a conclusion is invalid. The assumption of the present invention is that the exon mutation (this Does not rule out the role) (which has only a minor effect on the function of the gene) . This is simply due to the existence of functionally important variants of this gene. Emphasize that these studies can be negative.   On average, each candidate gene contributes only 0.5-8% of the variance of a given quantitative trait If (this depends on the phenotype and the size of the study), the results are moderate, border It can be line or negatively significant. But additive or superordinate Testing of two or more candidate genes for the effect of may show an even more significant effect.   A number of related studies simply include specific pairings in subjects compared to controls. Test the frequency of progeny. However, if the diagnosis is based on a complex set of symptoms, Certain alleles are significantly associated with some of the quantitative traits involved in diagnosis Get, but not with the diagnosis itself. For example, schizophrenia is a polygenic disorder In some cases, alleles of a particular candidate gene may have negative symptoms (eg, emotional flatness). ) Can be shown to be significantly related. This is present in some but not all cases Diagnosis of positive symptoms (eg, delusions or hallucinations) or schizophrenia itself It does not matter. Sub-syndromal quantitative trait test, not simple The limitations of analysis on simple dichotomous diagnoses are polygenic disorders. Genes that make a significant contribution to harm can be missed. Hybrid stress is also If there is no difference in the frequency of individual alleles in the role versus patient, It may allow a gene to have a significant effect on its phenotype (Comings and McM urray, 1997).   Hypotheses are most useful when they have immediate heuristic value. In related research One disadvantage of using highly polymorphic micro / mini-satellite polymorphisms is that many If each of the alleles, and even a greater number of potential genotypes, is examined, The ability of this study can be severely impaired enough to render it useless. Only And if the size of the iteration is a significant variable, even the maximum complexity of the polymorphism Homozygotes for shorter alleles, homozygotes for longer alleles , And heterozygotes. The present inventors Many genes in the trait (OB, MAOA, MAOB, CNR1, GABRA3, GABRB3, DBH, FRA Discover the value of this approach to studying the role of XA and NOS1) Was.   Although many potentially interesting candidate genes have been cloned and sequenced, For the most part, polymorphisms have not been reported in the Genome Data Base, Makes related research impossible. Based on this hypothesis, useful if the sequence is known One method for identifying micro / mini-satellite is to obtain the desired target from commercial sources. The goal is to obtain a large genomic clone carrying the gene. These are then: Can be screened for repetitive sequences that can be very beneficial in related studies You.   In this model, repetitive sequences that can form Z-DNA are useful in studies of multigenic inheritance. To prove to be the most useful polymorphism. This is the Z-hunt-II Screening for known sequences using the program (Schroth et al., 1992) Can provide important clues about the location of the most beneficial polymorphic regions. Hinting. To test this, we used this program to make NOS1 (Hall et al., 1994). Knockout mouse without NOS1 gene Based on the results of studies showing aggression in (Nelson et al., 1995), we Repetitive polymorphisms that we identified by visual inspection of the sequence of the NOS1 gene (Hall et al., 1994) were used to investigate various behavioral traits in humans. Some associations observed As such, we thought that: The polymorphism we used was Whether identified by the Z-hunt II program; and may include beneficial polymorphisms Whether other regions are present in this gene. Both predictions were true. Various lengths NOS1 (CA) n allele plays a role in NOS1 gene function Based on the hypothesis, we reduced this allele to the shortest (<199 bp) of 50% Alleles and two glues consisting of the longest (≥199 bp) 50% allele Grouped. Preliminary studies suggest some associations with behavioral phenotypes. Then We used the published sequence of the NOS1 gene as a Z-hunt-II algorithm (Wang 1979) was used to screen for the Z-DNA region. This is the invention Showed that the polymorphism used was one of three high Z-DNA content regions . A second region with a higher Z-score is a new region that was not previously detected. A typographic region was identified.   These three examples illustrate how model predictions are involved in polygenic disorders Whether it can lead to the acceleration of the identification of the gene to be performed is illustrated from a practical viewpoint. Human Genome  The use of this model in connection with sequencing data readily available from Project Ability to identify the presence of micro / mini satellites in close proximity to known candidate genes The increase could greatly contribute to our knowledge about multigenic disorders .   The monoamine oxidase A gene (MAOA) and the VNTR polymorphism allele Divided into two groups. There are significant associations with many quantitative variables associated with a particular symptom There. The results were based on 351 Tourette syndrome probands, their relatives, and control. Shows the score of the manic symptom in the tool. Subjects carrying the longest allele There was a significant increase in scores in the body (Gade et al., 1997). (b) Drug abusers And use of the same polymorphism in the control group. Again, the longest alleles and drugs There was a significant association with substance abuse scores (Gade et al., 1997). (c) SCL-90 test -Based quantitative scores for anxiety and obesity gene (OB) microsatellite Association between polymorphic alleles is homozygous for <208-bp allele (left) Subject and homozygous or heterozygous for ≧ 208-bp allele (right) Divided into zygote individuals. (d) Event-related potential (ERP) P300 wave (μ volt) amplitude and , CNR1 cannabinoid receptor gene microsatellite polymorphism allele Between subjects homozygous for ≧ 5 repeat alleles (right), and , <5 repeat alleles (left) divided into homozygous or heterozygous individuals (Johnson et al., 1997). (e) Brown adult ADD score and GABA_A, B3 (GABRB3) The association between the scepter gene microsatellite polymorphism allele is> 185-bp vs. Subjects homozygous for the allele (left) and for <185-bp alleles Were divided into homozygous or heterozygous subjects. (f) Grade IQ and IQ Association of the FRAXA locus with normal alleles in random adults assessed by omings et al., 1997a, b, or c? ).                                 Example 27        For ADHD in subjects with or without learning disabilities     Additive effects of three adrenergic genes (ADRA2A, ADRA2C, DBH)   We have identified three adrenergic genes (adrenergic α2A). Receptor (ADRA2A), adrenergic α2C receptor (ADRA2C), and Dopamine β-hydroxylate (DBH)) and ADHD with learning disability (LD) and We tested for association or additive effects with and without ADHD.   These two types of ADHD and the potential candidates we have assigned to them The genes are summarized in Table 78. Plasma MHPG and language IQ (but not performance IQ) reported by Halperin et al. (1997). Correlates with lower verbal IQ scores in young delinquents, violence or other major Significantly similar to the finding that they stopped crime (Hirschi and Hindelang, 1997; Miller, 1988; Shulman, 1951; Moffitt and Silva, 1988). Plasma MHPG levels Negative correlation with low word IQ indicates that NA genes may also be involved in antisocial behavior Suggests.   Adrenergic α2 receptor is the site of action of clonidine And is abundant in the prefrontal and parietal attention centers, and synaptic NA turnover Play a role in the regulation of α2A (ADRA2A), or adrenergic α2C (ADRA2C) receptor, or Whether the dopamine β-hydroxylase gene is associated with ADHD itself, and ADHD + Attempted to determine whether a preferential association with cognitive impairment subtype exists. The present inventors have found that MspI polymorphism in the promoter region of the ADRA2A gene (Lario et al. , 1997), the dinucleotide repeat polymorphism of the ADRA2C gene (Riess et al., 1992), and D The TaqI B1 / 12 polymorphism of the BH gene (d'Amato et al., 1989; Wu et al., 1997) was used.   Method. Genotype frequency of single base pair polymorphism in ADRA2A gene and DBH gene, Genotype frequency of dinucleotide repeat polymorphisms in the ADRA2C gene and 325 subjects Body (267 individuals have Tourette's syndrome and 58 are normal controls) Was determined. Parental or self-reported questions on behavioral variables for ADHD and LD Evaluation was made by vote and personal interview. Assess possible relationships for antisocial behavior For this purpose, behavioral and rebellious behavior disorder symptoms were also assessed.   The study group consisted of 325 unrelated subjects. 267 of these Meet the criteria of DSM-III-R and DSM-IV for Tourette's syndrome, and D.E. All had personal interviews with .C. The remaining 58 were controls. Not all latte He was a Caucasian. TS subjects were treated at the City of Hope Medical Center I came from the Syndrome Clinic. We have previously described our TS subjects as light Grade (grade 1, chronic tics too mild to treat), moderate (grade 2, Severe enough to require treatment), and severe (grade 3, some (A very significant effect on some aspects) (Comings, 1990; C omings and Comings, l987b; Comings and Comings, 1984). Of TS subjects , 25% are grade 3, 12% are grade 1, and the remaining 71% are gray Card 2. TS and ADHD are similar obstacles, and most visiting clinics A number of TS subjects have co-morbid ADHD (Comings, 1990; Comings and Coming s, 1987b; Comings and Comings, 1984). Control, TS coating without ADHD Test subjects, and the presence of TS subjects with ADHD, Especially sufficient to examine the association between the gene and ADHD as a continuous trait variable Make it appropriate. Both TS subjects and controls are described in detail elsewhere. (Comings et al., 1996j; Comings, 1994a; Comings, 1994b; Comings, 1995a) Comings, 1995b). The average age of TS subjects was 18.0 years (S.D. 13.2). The majority were older children and adolescents, but 29% were 21 or older. Control The average age of the children was 46.3 years (S.D. 15.38).   Each control and TS proband had all DSM-III, DSM-III-R for ADHD , And were required to fill out a questionnaire that included an evaluation of the DSM-IV criteria. Than For older subjects, the question referred to when they were children. ADHD score Was based on the DSM-IV (1994) standard for ADHD. In the question, children and Whether these symptoms were absent or rare during adolescence ( Score = 0), occasionally present (score = 1), or always present (score = 3) Asked). With all three responses, among those of all degrees of severity All identifications were provided. ADHD scores are based on DSM-IV carelessness, impulsive symptoms, And overactive symptoms.   If the child is under 14 years of age, the parent fills out the questionnaire, while subjects over 14 years of age Filled out questionnaires on their own or with the help of their parents. The questionnaire is And the family members themselves were reviewed to ensure their accuracy.   Subjects were asked three questions to assess the existence of a problem with the paired disorder. Did. 1) You have ever had an Education Handicap (EH), a learning Handicap Have you been placed in a special class (LH) or learning disability (LD)? 2) you Have you ever been in a resource class? 3) you ever Have you been told that you have a learning disability? For each question, No = 0 or Score = 1, and additionally an LD score was created. In California, The placement in any of the special classes above may be performed by one or more educational psychologists. Requires an assessment and an assessment that the student is more than two years behind his peers .   To assess academic performance in elementary school, subjects "In grades 1-6, compared to the overall average, Was your performance below or above the average? : A) math, b) reading C) Write down. " Responses for a to c are above the average = 0, average = 1 , And below average = 2 and summed to get GSAP score .   Similar 0, 1, and 2 DSM-IV groups for behavioral disorders and rebellious behavior disorders Semi-grading was used.   Subject has attention deficit / hyperactivity disorder, mixed type; Subject meets significant AD if DSM-IV criteria for predominant overactive urge type are met Deemed to have HD issues. Subject is placed in one of the above special classes If the subject has a learning disability, I considered it. Subjects meeting the criteria for ADHD and learning disability were identified as A + LD + Classified as group. Do not meet the criteria for ADHD but meet the criteria for learning disabilities Filling subjects were classified as A-LD + group. Meets the criteria for ADHD, but Subjects that did not meet all of the criteria were classified into the A + LD-group. Finally, any group Subjects that did not meet the criteria were classified as A-LD-group. Similar grouping, GSAP Used on a core basis, where those with a score of 0-4 are scored as GS- And those with a GSAP score of 5-6 were scored as GS +.   The questionnaire (Comings, 1990) contains quantitative variables related to ADHD, Bus score, learning problems, elementary school achievement, disability, and rebellious behavior It is intended to provide a highly structured method of providing. For symptom evaluation The accuracy, usefulness, and sensitivity of the questionnaire-based approach were the same structured By comparing the use of such equipment to the interviewer's application of the equipment, others ( Gadow and Sprafkin, 1994; Grayson and Carlson, 1991) I have. The inventor's review of the questionnaire for each subject was It is shown that the information obtained more accurately reflects.   ADRA2A using single base pair MspI polymorphism in promoter region (Lario et al., 1997) And divided into genotypes. Their PCR^TMConditions and primers were used. ADRA2C, Dinucleotide repeat polymorphisms and PCR^TMGenotype using procedures (Riess et al., 1992) divided. Polymerase chain reaction (PCR^TM) Using 0.1 μM of each fluorescent label The target DNA was amplified using a mer. PCR^TMDilute the product with 100 μl deionized water and 0.5 μl, 75 μl formamide + 9.5 μl ROX standard + 9.5 μl blue dextrin 2.5 μl of the mixture of dyes. This was denatured at 92 ° C for 2 seconds, And use the sample as an Applied Biosystems 373 DNA Sequencer (Applied Biosyste ms, Inc., (ABI) Foster City, CA) on a 6% PAGE and run the gel on a 120% Electrophoresed at 0 volts and constant 30 W for 4 hours. Pre-treat gel and internal standard (ROX 500). Peaks to fragment color and size Genotype Classifier (genotyper) (version 1.1) (Applied Biosystems, Inc.). This is in addition to some very minor alleles Major alleles at 183 bp and 185 bp, and less frequently 181 bp alleles Spawned a gene. These were divided into three genotypes: ≦ 183 / ≦ 183 bp = 1, Terozygote = 2, and ≦ 183 / ≦ 183 bp = 3.   DBH gene genotyped for TaqI B1 / B2 polymorphism (d'Amato et al., 1989) . This originally required Southern blotting on labeled DBH clones, The present inventors, PCR this^TM(Wu et al., 1997).   Genotyping of the dopamine genes (DRD2 and DATI) has been described previously ( Comings et al., 1996). For the DRD5 gene, we have Polymorphisms and techniques (Sherrington et al., 1994) were used.   Three statistical analyzes were performed. First, evaluate the effects of ADRA2A and ADRA2C genotypes Sum of each gene scored as 11 = 2, 12 = 2, and 22 = 3 ANOVA was performed on the ADHD score. Once you have selected genotype grouping, Assigned a dichotomous variable to a gene to indicate the presence or absence of the associated genotype . A2A + A2C scores were generated to evaluate the additive effect of the two genes. Where A of 0 Those with a DRA2A score and an ADRA2C score of 0 are 0. 1 ADRA2A score A and 2 with an ADRA2C score of 1. For any gene Those with a score of 1 were scored as 1. NA gene scores are Was added to all three NA genes.   To eliminate the need for Bonferroni correction, all six behavioral scores The group was examined using MANOVA. This is done separately for each gene and multiple The genes went together. The genes described individually and together by each gene To obtain an estimate of the% of core variance, a linear regression analysis was performed on individual Each gene score, A2A + A2C gene score, and NA gene score I went. Based on the priori hypothesis that the effects of NA genes are additive , A linear ANOVA (polynomial subcommand 1) is replaced with the ADRA2A gene and the ADRA2C gene, or the ADRA2A gene and the ADRA2C gene. The results of the addition of the gene and the DBH gene were performed. Notably different at α = 0.05 A post-hoc tukey analysis was performed on the resulting means. All statistical tests were performed using SPSS This was performed using a statistical package (SPSS, Inc., Chicago, IL).   result. ANOVA was performed to determine the effect of ADRA2A genotype on ADHD score Was. The average score for those carrying 11 genotypes is 17.4 (n = 180, s.d. = 11.1) and 19.05 for 12 genotypes (n = 125, S.D. = 10.52) , And 22.05 for 20 genotypes (n = 20, S.D. = 11.167), F ratio = 2.05, p = 0 It was .13. For MANOA, the ADRA2A gene was transformed with 11 = 1, 12 = 2, and 22 = 3 As scored. For regression analysis, this was calculated as 11, 12 = 0, and 22 = 1 As scored.   MANOVA was performed on six scores (Table 80-A). Significant associations were LD, GSA P, impulses, and all MANOVA. Linear regression analysis for ADHD, LD, GSAP, CD, And ODD scores (Table 3). LD and GSAP scores are significant phases There was a Seki. If the Bonferroni corrected α of 0.05 / 5 or 0.01 is LD, The core remained significant.   ANOVA was performed to determine the effect of ADRA2C genotype on ADHD score. 11 remains The average score for those who possess the variant is 18.9 (n = 122, S.D. = 10.41), 12 15.90 for genotype (n = 112, S.D. = 10.99), and 20.5 for 22 genotypes 4 (n = 91, S.D. = 11.1), F ratio = 4.90, p = 0.0080. After this, the Tukey test Thus, the mean for 12 heterozygotes was significantly greater than 11 or 22 homozygotes It was low. This indicates the presence of negative heterosis (Comings and M acMurray, 1998). Therefore, for linear regression analysis, ADRA2C gene was 12 = 0 and Scored 11 or 22 = 1.   MANOVA for ADRA2C gene score was performed for 6 behavioral scores ( Table 80-B). Significant associations were inattention and impulses. Linear regression analysis (Table 81) Showed a significant correlation for the ADHD score. If α = 0.01, ADHD score Was still significant.   The present inventors have identified a dopamine B-hydroxylase gene in a TS-ADHD subject. Previously studied (Comings et al., 1996j) and the presence of the Taq B1 allele (d'Amato Et al., 1989) found to be associated with ADHD. Therefore, we have identified the DBH gene The offspring were scored at 22 = 0 and 11 or 12 = 1. According to MANOVA (Table 80-C), The deviation score was also not significant. By linear regression analysis, correlation with GSAP score It was significant. At α0.01, nothing was significant.   To investigate possible additive effects of both adrenergic α2 receptor genes For this, the scores of the individual genes were added to create an A2A + A2C score. 325 subjects Of the bodies, 106 (32.6%) have a score of 0 and 205 (63.1%) have a score of 1. And 14 (4.3%) had a score of 2. A2A + A2C score and 6 The results of MANOVA for individual behavior scores are shown in Table 80-D. The result is carelessness, impulse , Overactivity, GSAP, LD, and ODD scores. Linear regression analysis According to Table 81, the correlation was significant for ADHD, LD, GSAP, and ODD scores. Was. At α = 0.01, the ADHD, GSAP score remained significant. All except CD score Linear ANOVA analysis for all patients with 0, 1, or 2 variant genes Progression in all scores, progressing from the test subject, was indicated. ADHD, carelessness, impulses, Hyperactivity and GSAP scores were all significant at p <0.01.   To study the possible additive effects of the three adrenergic genes, ADRA2A, The NA gene score was created by adding the scores of the ADRA2C and DBH genes. 325 Of 36 subjects, 36 (11.1%) had a score of 0 and 132 (40.6%) had a score of 1. Had a score and 145 (44.6%) had a score of 2 and 12 (3.7% ) Had a score of 3. MA for NA gene score and 6 behavioral scores The results of the NOVA are shown in Table 80-E. Inattention, Impulse, Overactivity, GSAP, LD, and ODD All scores were significant. By linear regression analysis (Table 81), ADHD, LD, The scores for GSAP and ODD were significant. At α = 0.01, ADHD, GSA P and ODD scores remained significant.   ADHD subscore, LD, GSAP, and ODD scores for NA gene scores Linear ANOVA analysis of subjects with 0, 1, 2, or 3 variant genes It showed that there was a gradual increase in all scores straddling. ADHD, hyperactivity, Carelessness, urge, GSAP, and ODD scores were all significant at p <0.01.   We used linear ANOVA to identify four groups (ADHD-LD-, ADHD + LD-, ADHD-LD +, And ADHD + LD +)^TwoAnalysis was carried out. These results , And Table 82. This indicates that the frequency of subjects carrying all three variant NA genes Across these groups, from 0.6% for the ADHD-LD- group, To 5.4%, to 7.7% for the ADHD-LD + group, and to 11.4% for the ADHD + LD + group Showed increased. The frequency of subjects not carrying the variant NA gene It decreased from 14.4% to 8.9%, 7.7% and 2.9% across the four groups. line Shape trendχ^TwoWhen testing the entire 4 × 4 table by analysis (Cochran, 1954), P = 0.0005. When A-LD + and A + LD + groups are combined,^Two= 17.6, d.f. = 6, p = 0.007, and linear trend χ^Two= 12.9, d.f. : 1., P = 0.0003.   Association between NA genes and GSAP scores is often greater than association with LD scores So we also examined the crosstabulation between the GSAP score and the NA gene score Was. This indicates that the frequency of subjects with a NA gene score of 3 has a GSAP score of 0-2. From 1.6% for subjects with a score of 3-4 Is in the range of 0.8% and 11.8% for subjects with a score of 5-6. Indicated. Linear χ over the entire range of both scores^TwoIs significant at p = 0.004 Was. Therefore, independent of the presence or absence of ADHD, two or three Children with below-average grades in subjects in this class are likely to carry variant NA genes It was the highest.   Subjects were divided again into four groups to determine the effect of the presence or absence of ADHD Was. Here, those having a GSAP score of GS + = 5 or 6 and a GSAP of GS− = 0 to 4 Have an SAP score, and the four groups are A-GS-, A + GS-, A-GS +, and A + GS +. Χ for NA score^TwoThe results of the analysis are shown in Table 83. 3 NA genes Frequency with core ranges from 0.6% to 2.4%, 4.8%, 12.5% across the four groups Increased to Linear χ for 4 × 4 table^TwoWas significant at p = 0.0003.   We believe that the average in elementary school in math, reading, and writing is The results of the lower grades were examined separately. This is assuming above average = 0 and below average = 1. NA genetics for scoring math, reading, and writing performance ス コ ア of child score^TwoPerformed by analysis. About Math, Pearson^Two= 9.17, p = 0.027 , Linear χ^Two= 4.18, p = 0.04. Read about Pearson II^Two= 15.14, p = 0.0017 , Linear χ^Two= 13.14, p = 0.0003. About writing, Pearson^Two= 13.18, p = 0.00 4, linear^Two= 10.54, p = 0.001. Therefore, below average performance in all three domains Was significantly associated with the NA gene score, but the effect was up to Yes, then dictation, and least about mathematics.   For comparison, we also adjusted the dopamine gene score for each subject. Solid. Read about Pearson II^Two= 12.08, p = 0.007, linear χ^Two= 8.24, p = 0. 004. About Math, Pearson^Two= 2.90, p = 0.41, linear χ^Two= 2.21, p = 0.137. book About Pearson II^Two= 11.11, p = 0.011, linear χ^Two= 0.02. Therefore, The Min gene also played a role in reading performance, and in math performance Plays a much smaller role.   To determine the relative importance of NA to the dopamine (DA) gene, we Included DA gene scores in MANOVA (Table 80-F). Careless for all six genes Impact, overactivity, GSAP, LD, behavior, and ODD scores were all significant. Was. Linear regression analysis for all six genes (Table 81) revealed ADHD, LD, GSAP , And ODD scores were significant. As previously shown (Comings et al., As in 1996), the dopamine gene plays an important role in ADHD. this thing Was confirmed for the three DA genes used herein. These are ADHD Accounts for 2.5% of the core variance, and when added to the NA gene, all six variances Accounted for 6.1% (p <0.0001). In contrast, the DA gene is associated with LD and GSAP scores. Played little role in However, for the GSAP score, Fraction from 3.4% for 3 NA genes alone, when DA gene is added Increased to 4.2%. DA gene plays little role in behavioral score However, they played an important role in the ODD score, accounting for 2.6% of the variance (P = 0.004). All six genes accounted for 4.9% of the variance in the ODD score (p = 0 .0001).   When we examined the frequency of three DA genes in four ADHD: LD groups, three All genes were 10.0% ADHD-LD- group, 19.8% ADHDfLD- group, 15.4% ADHD-LD + Group, and 17.1% of the ADHD + LD + group. Thus, in contrast to the NA gene, 3 There was no escalation across the two groups. For the entire 4x4 table, Pearson II^Two = 10.48, d.f. = 9, p = 0.31, and linear χ^Two= 0.90, d.f. = 1, p = 0.34.   MANOVA measures carelessness, impulses, overactivity, learning disabilities, primary school achievement, and rebellious behavior. There was a significant association between the quantitative score for movement and the examined NA genes. Most The major association (p = 0.0003) was for the additive effect of all three genes. ADHD A + LD, A-LD +, A + LD + (p = 0.0005), there was a significant increase in a number of variant NA genes, There was no comparable effect for the dopamine gene.   Consideration. Different regions of the brain, different neurotransmitters, and different sets of genes Two subtypes of ADHD involved (one with cognitive deficits and the other without) Identification (Table 80) has significant diagnostic and treatment value in the medical care of ADHD children. I can do it. However, ADHD is based on multiple variant genes inherited from parents (Comings, 199 Keep in mind that it is a polygenic disorder with 6b) (Comings, 1996a) Must. Similarly, in most children and adults with both types of components, There seems to be duplication.   However, as shown in Tables 82 and 83, NA metabolism and deletion of the variant NA gene May be more involved in ADHD children with cognitive deficits than in ADHD children without cognitive deficits More likely.   Looking at the additive score may also indicate that the gene happens to be a given subject or subject. Different genes do not play a role in the body but have similar functions In this case, there is an advantage that both effects can be included. This is sufficient for this study. Minutes. For example, the phenotypic effects of each of the three NA genes can be examined separately. Where significant levels of MANOVA are appropriate (Tables 80-A, 80-B, and 80-C) , And the correlation coefficient is often assigned to the five scores examined by linear regression analysis. None of the Bonferroni corrections could be tolerated (Table 81). However, ADRA2A genetics Either offspring and ADRA2C gene or ADRA2A gene and ADRA2C gene and DBH gene When was added, the results were robust. This is also a gradual additive effect This was the case when tested by ANOVA. Using the ADHD score as an example, Quantitative regression analysis shows that each gene individually accounts for only 0.7-2.6% of the variance of the quantitative score. (Table 82). However, the ADRA2A and ADRA2C genes were added. If they account for 3.3% of the variance (p = 0.001), and all three NA genes When added, they accounted for 4.0% of the variance (p = 0.0003). Three dopamine Genes account for 2.5% of the variance in the ADHD score, and all six genes together If so, they accounted for 6.1% of the variance (p <0.0001). This means that Shows that offspring and the DA gene play an additive role in ADHD.   Twin testing suggests that additive genetic effects account for> 70% of ADHD (Sh Erman et al., 1997a; Sherman et al., 1997b; Gillis et al., 1992). This is the three NA genetics Offspring account for about 6% of the genetic component of ADHD, and NA + DA genes account for about 10% Indicates that the component was occupied. This may seem less, but more The percentage continues to rise as more genes are added (Comings et al., 1998). Six Genes account for only 6.1% of the variance in ADHD scores, but based on a correlation coefficient of 0.25 Thus, depending on other variables, these six genes predict up to 25% for ADHD Note that it has accuracy.   The additive effect of NA genes also shows that the% variance increases from 1.0 to 1.6 for individual genes. % Was impressive with GSAP scores increasing to 3.4% for all three.   The results shown in Table 83 are across the A-LD-, A + LD-, A-LD +, and A + LD + groups. Shows a gradual increase in the frequency of subjects carrying two or more variant NA genes You. However, an alternative hypothesis is that the ADHD + LD group or ADHD + any other concurrent disorder group Simply indicates a group with more genetic burden for all ADHD genes That is. The present inventors have reviewed the scores for three different dopaminergic genes. By determining whether a shows the same gradual increase across three groups, This alternative could be assayed. In subjects, we found six different dopamine residues. Of the genes (DRD1, DRD2, DRD3, DRD4, DRD5, and DAT1), DRD2, DAT1, and DAT1 And DRD5 were observed to have the most significant additive effect on the ADHD score. Pieces Each of these accounted for 0.5% to 1.0% variance, while together they accounted for 2.5% variance. I did. Therefore, we have created a dopamine gene score that is also in the range of 0-3. Done. The percentage of subjects carrying all three variant genes was 10% for the A-LD-group. From 1.0% to 19.8% for the A + LD- group, 15.4% for the A-LD + group, and Range was up to 17.1%. Thus, in contrast to the alternative hypothesis, A + LD + Increased genetic load for these three dopamine genes in the group compared to the A + LD- group No load was present. In addition, for the entire range of dopamine gene scores, But a linear trend.^TwoBut the results were significant. This translates into a NA gene score About linear^TwoIn sharp contrast to p = 0.0005. These results indicate that the NA gene is ADH It is preferentially involved in D + LD individuals, while the dopamine gene may have cognitive deficits. Halperin-Pliszka supports the notion that the presence of a germ is equally involved in ADHD We further support hypothesis b.   A further consideration is the math, reading, and writing skills of individuals at primary school. Simply examining the same as whether or not they are in a special LD class, The purpose is to give good separation by the number of variant NA genes. When examined separately, This effect is greatest in reading, almost equal in writing, and is It is the least in the achievements. These results average reading, writing, and math. Primary school children with full-blown ADHD are most likely to carry variant NA genes Suggests high children. This is also the treatment of such children's academic problems Suggests the need for a long-term, double-blind study of the efficacy of clonidine in rats. The personal clinical experience of one of the inventors (D.E.C.) has shown a period of several months. Thus, percutaneous treatment of poorly performing ADHD children with clonidine alone is a significant achievement Can result in an increase.   The link between low-language IQ and aggressive youth antisocial behavior has been replicated in many studies (Hirschi and Hindelang, 1977; Miller, 1988; Shulman, 1951; Moffit t and Silva, 1988; Moffitt, 1990). This association between low-language IQ and delinquency Control economic factors, race, academic achievement, and motivating factors to take exams It is shown even after doing this (Moffitt, 1993). Moffitt and Silva (Moffitt And Silva, 1988) also found that the link between low IQ and delinquency was easier for police officers. The captives shown are not an artifact of dull delinquency. why Unaware delinquents identified by the interview should also have a low IQ Is found. The present inventors report that the NA gene is Tested for possible association with behavioral disorders. Any of the three genes and behavioral disorders There was no significant association with Was.   The use of subjects with TS to study ADHD has potential benefits and And disadvantages. The practical benefit is that we have 1,500 TS patients Is to have a large collection of DNA samples that exceed Diagnostic Interview Schedule (Robins et al., 1981) and DSM-IIIR standards Has completed a comprehensive and highly structured questionnaire. This is because the inventors It allows to select subjects with relatively severe symptoms for the study. Obedience Therefore, they may have a higher genetic burden than subjects with minimal symptoms Is higher. The use of more extreme phenotypes is widely recommended in genetic studies. To (Risch and Zhang, 1996; Plomin et al., 1994). Most of the clinic referrals Not all TS patients (Comings and Comings, 1984; 1987b; Knell and Coming s, 1993) also have ADHD, so this has ADHD, and None, a set of subjects is provided. It examines the full range of quantitative ADHD traits It is particularly useful for our approach. Because this is only for ADHD subjects It provides a wider range of scores than studied (Comings et al., 1996j). TS The population also has ADHD, behavioral disorders, and rebellion in both TS probands and their relatives. The frequency of concurrent illnesses such as sexual behavior disorders and learning disorders is high, (Knell and Comings, 1993; Comings and Comings, 1987a; Comings, 1995a Comings, 1995b). Biederman and colleagues discuss ADHD probands and their relatives. (Biederman et al., 1990a, b; Biederman et al.) , 1993). Potential disadvantages of using TS samples are clinical and genetic Despite considerable overlap in aspects (Comings and Comings, 1993), ADHD subjects with ticks have a slightly different set than ADHD subjects without tics. It is possible to have a variant gene of the above. Thus, ADHD subjects without tics It is important to repeat these findings in Further limitations of this study Credibility for parent and self-reported questionnaires. WISC-R, WRAT-R, and Studies using other direct tests are preferred. However, in our experience, we have studied and Based on actual personal interviews for all subjects, these questionnaires Accurately reflect the behavior of each. Furthermore, the present inventors have found that A case in which a child without problems was placed in an EH, LD, LD or special education class We have not observed so far, so we have no idea about the LD score in this manner. The assessment is considered to represent a robustness test for the presence of cognitive impairment. Ironically, children Is below average in two or more subjects (math, reading, writing) in elementary school Assessment of presence or absence is better for NA gene score than for LD class Provided good separation. This is because the actual class performance is not reliable for cognitive abilities. Many children with poor academic achievement never go to special classes Indicates that it cannot be entered.   There are very few 22 homozygotes in the ADRA2A gene and therefore a small number of subjects Possesses both adrenergic α2 genes or all three NA genes The results are scored and the results are higher in these less homozygotes. We can argue that it can be brought about by the accidental existence of a. Test for this For this reason, we also scored the ADRA2A gene as 11 = 0 and 12 or 2 = 1. Attached. When combining two α2 genes using this scoring, MANOVA Are associated with carelessness (p = 0.010), impulses (p <0.001), and hyperactivity (p = 0.021). Was still significant. And by linear regression, this combination is still It accounted for 3.1% of the variance (p = 0.0014). ADRA2A gene scored in this manner Has a NA gene score of 3 if added to the ADRA2C and DBH genes There were 66 subjects. MANOVA is inattentive (p = 0.001), impulses (p = .001), And overactivity (p = 0.004) scores. By linear regression analysis , This NA score accounted for 4.1% of the variance (p = 0.0002). These results are The appearance of a high-scoring chance in ADRA2A 22 subjects with few Indicates that it is not due to   The present inventors have found that this finding has some additional implications that were not included in this study. It is intended that it can be emphasized by adding NA genes. These are Norr Drenaline transporter (NT), adrenergic α1 receptor (ADRA 1A-ADRA1D), and the PNMT gene, all of which are Plays a role in regulating pus NA levels.                                 Example 28                 With attention deficit hyperactivity disorder and Tourette's syndrome Association with neuronal nicotine acetylcholine receptor α4 (CHRNA4) gene   Introduction. Nicotine stimulates the dopamine reward pathway and increases attention, alertness, learning, and memory. Enhances memory and is useful percutaneously in the treatment of Tourette's syndrome and ADHD It is an addictive drug that has been used. Nicotine acetyl, the most prominent neuronal form The choline receptor is α4β2. The present inventors have studied the nicotine activity of neurons. Genetic variants in the chillin choline α4 receptor CHRNA4 gene We hypothesized that it might be associated with Syndrome.   Neuronal nicotine acetylcholine receptor is located around the central channel (Α2 to α9) and β (β2 to β4) subunits ( Unwin, 1993). α subunit is a muscle-type nicotine acetylcholine receptor As with the α1 subunit, it carries a pair of cysteines. The β subunit is Has no cysteine in this pair. Major neurons nicotine acetylcholine re The scepter subtype is composed of α4 and β2 subunits (Whiting et al., 1). 991; Schoepfer et al., 1988). α4 and β2 are most widely expressed in the brain (Wada et al., 1989; Whiting and Lindstrom, 1988; Whiting Et al., 1991), the present inventors set out the CHRNA4 gene in Tourette's syndrome and ADHD. An attempt was made to examine the association between offspring alleles and the CHRNB2 gene. The proper polymorphism is Only available for the CHRNA4 gene (Weiland and Steinlein, 1996) This is the gene examined by the present inventors.   Method. We studied 282 unrelated non-Latin Caucasian Turret syndrome subjects. In complex VNTR polymorphisms of the CHRNA4 gene in somatic and 63 controls Allele associations were examined. Study group consisted of 345 unrelated subjects Was. Of these, 282 met the DSM-IV criteria for TS and all were D.E. Interviewed personally with .C. The remaining 63 were controls. TS subjects are Cit From the Tourette Syndrome Clinic at the y of Hope Medical Center. These are AD Example 27, addressing the role of the norepinephrine gene in HD and learning disabilities From the same group of subjects listed. In the presence or absence of ADHD and learning disabilities Behavioral scores and segregation are as described in that document. ADHD score is , Based on the DSM-IV (Diagnostic, 1994) standard for ADHD. In the question, These symptoms were absent or rare during childhood and adolescence. Was present (score = 0), occasionally (score = 1), or always ( Score = 3). With all degrees of severity using all three responses Provided all discrimination between those. ADHD scores are based on DSM-IV The sum of dynamic symptoms and hyperactive symptoms.   CHRNA as described in Welland and Steinlein (Weiland and Steinlein, 1996) The polymorphism in the first intron of the four genes was used. PC reported by them R^TMPrimers and conditions were used. In a study of 88 unrelated whites, they found that 1 Fourteen alleles ranging in length from 96 to 264 bp were identified (see Table 84).   Polymerase chain reaction (PCR^TM) Using 0.2 μM of each fluorescently labeled primer Was used to amplify the target DNA. PCR^TMDilute the product 10-fold with deionized water and add 0.5 μl Diluted with 75 μl formamide + 9.5 μl ROX standard + 9.5 μl blue dextrin Added to 2.5 μl of the mixture made from the dye. Change this at 92 ° C for 2 minutes. And samples are run on an Applied Biosystems 373 DNA sequencer (Applied Biosystems 373 DNA Sequencer). d Biosystems, Inc., (ABI) Foster City, CA) on a 6% PAGE and The gel was run at 1200 volts and a constant 30 W for 5 hours. Pre-treat the gel and And analyzed using an internal standard (ROX 500). The peaks are Genotype classifier based on size and size (version 1.1) (Applied Biosystems, Inc. .).   result. We have identified 345 individuals in this study and the number in other studies. One hundred people were genotyped. Not surprisingly, Wellland and Steinlein (Weiland and Steinlein, 1996), in addition to those described by the present inventors. Found a number of additional alleles (21 total). 17 of these are Was observed in subjects in this study. Welland and Steinlein (Weiland and And Steinlein, 1996) use silver staining, and contradict the gel from top to bottom. As we started counting genes, their lower-numbered allele was up to bp, The allele with the highest number was the smallest bp. ABI sequencer As the band scans as it reaches the bottom edge, our hands In order, the lower numbered allele showed the lowest bp allele, but the lower numbered allele. Large alleles are the largest alleles. We first discovered Welland and S. An alternative to using the same numbering system as teinlein (Weiland and Steinlein, 1996). All attempts have been made, but the size of the allele in bp based on This was difficult because they differed in value). Therefore, the present invention We used the ABI numbering system, and for comparison purposes we used 2 Two nomenclatures are listed in Table 84.   Table 85 shows the four PCRs for the different alleles.^TMProduct sequencing results are shown. You. This illustrates the complexity of this VNTR polymorphism.   Among all major alleles, the frequency of 9, 12, 14, and 16 alleles was TS test High in the body, while the frequencies of the 13, 15, and 18 alleles It was expensive. 17 allele 対 立^TwoAccording to the analysis,^Two= 33.65, d.f. = 16, p = 0.006 1. Analyzes were performed at a frequency of 0.05 or more in either control or TS subjects. If alleles are restricted to^Two= 71.6, d.f. = 6, p <0.0000001. Allele frequency The largest difference in degrees was for allele number 9.   Keep analysis straight and test quantitative variables as well as homozygous versus heterozygous To enable effects of conjugation and to generate variables for regression analysis In addition, the CNRNA4 gene score was calculated as follows: x / x genotype (non 9 / non 9) = 1, 9 / x = 2, And 9/9 = 3.   Behavior investigated in Example 28 for the norepinephrine gene (Comings et al., 1998) In addition to the set of variables, we also determined the total tick score (Comings et al., 1996 ). The association between CNRNA4 gene score and these variables was determined using MANOVA. And examined at the same time. The results (Table 86) show the CNRNA4 gene, elementary school achievement (GSAP), and learning. A significant association between disability (LD), rebellious behavior (ODD), and overactivity score Showed that it exists.   To assess the role of different genotypes on these scores, MANOVA Significant total ADHD scores with p <0.1 and post-hoc ANOVA analysis of each variable were performed (Table 87). This This indicated that all scores were maximal for 9/9 homozygotes.   A further question is whether there is any association between the CNRNA4 gene and smoking As a result, we have identified two variables in subjects older than 17 years, Have you ever smoked? "And" The number of smoking boxes per day " . None is significant, and the average number of smoking boxes per day is not significant for other genotypes. It was 0.10-0.20, whereas it was 0.5 for 9/9 homozygotes. 9/9 homozygous Since there were only 9 subjects who were bodies, more samples showed significant results Can be given.   ADHD-LD-, ADHD + LD-, ADHD-LD +, and ADHD + LD + CN of three CNRNA4 genotypes^TwoWhen examining the analysis, the frequency of the 9/9 genotype was in the ADHD-LD-group Out of 5.6%, 6.0% for ADHD + LD- group, 7.1% for ADHD-LD + group , And 13.5% for ADHD + LD +. The total correlation is Pearsonχ^Two(P = 0 .385) is not significant and is linear^TwoSignificance border (p = 0.051) It was a line. Therefore, the examined norepinephrine gene (Comings et al., 1998 Contrary to), the CNRNA4 gene plays a role in the type of ADHD-LD associated with the parietal lobe There was little evidence of success.   Univariate regression analysis using genotype variables for total ADHD scores also produced the following results: Done: r = 0.123, r^Two= 0.015, T = 2.30, p = 0.022. 9, 12 in TS subjects There is an increase in the frequency of alleles 14, 14, and 16, with the maximum for 9 alleles And increases in the 13, 15, and 18 alleles in the control There were 13 alleles, the largest.対 立 all alleles^TwoCompared by In these cases, they differed significantly at p = 0.002. Conflicts with a frequency greater than 0.05 When comparing only genes, this group^Two= 71.6, d.f. = 6, p <0.0000001 significant Was different. Genotype grouping based on 9 alleles (9/9, 9 / x, x / x) Eight quantitative scores related to ADHD, ticks, behavior, and learning Investigated by VA. Related are primary school achievement, learning disabilities, rebellious behavior, and overactivity The scores were significant. ANOVA indicates that all scores are 9/9 homozygous About the maximum. Linear regression analysis of genotype scoring The CHRNA4 gene occupying up to 1.5% of the variance (a) (p = 0.022) was shown.   Conclusion. These results indicate that the CHRNA4 locus is at risk for ADHD and TS. Suggests that it is one of multiple gene sets of contributing genes.   PCR used in these studies^TMThe sequencing of the amplified segment Very complex polymorphisms that involve both size differences and sequence differences Is shown. Repeated polymorphisms themselves may play a role in the regulation of related genes. this is , Based on the tendency of these repeats to form Z-DNA. Both repeat length and sequence Changes in Z-DNA formation that play a role in gene regulation in a number of ways It plays a role in determining the quantity (Comings, 1997). The complex examined here Polymorphisms showed significant changes in both size and sequence. By itself, This may be uniquely relevant for related studies.   To avoid loss of ability to participate in the independent evaluation of many other scores, We analyzed their analysis with the same behavioral score + total ticks as examined in Example 27. Limited to score. This is because nicotine has been used to treat tics. Was added to determine if the gene was associated with the tic itself. For MANOVA And evaluated the scores as a group to avoid the need for Bonferroni correction. this is, Significant associations with four of the eight scores were shown (Table 86). ANO after hoc for each variable When VA studies were performed, the scores were highest for 9/9 homozygotes. Combined The results show that CHRNA4 was found in ADHD and TS, and especially in TS subjects with ADHD. , One of the genes that plays a role as a genetic risk factor Hinting. Regression analysis suggests that ADHD scores can contribute up to 1.5% of the variance You.   CHRNA4 is more about learning disabilities and primary school achievement than ADHD subscore Showed a strong association with the norepinephrine gene examined in the relevant literature Different, with or without ADHD, and with or without learning disabilities Most, but not all, of the gradual increase in the frequency of 9/9 genotypes across the four groups There was no evidence.   We found that the genotype grouping described increased the expression of the CHRN4A gene. Although we still do not know whether it is associated with Supports the clinical efficacy of nicotine for HD and TS symptoms. In other populations, Control and the difference between TS and ADHD It is also likely that some could be involved. Across multiple samples, The most reproducible results are consistent with controls on TS or ADHD subjects. Χ of allele frequencies^TwoIt can be an analytical comparison.                                Example 29              VNTR allele length and X-linked MAOA gene           Correlation of phenotypic effects in Tourette syndrome and drug abuse   Introduction. Abnormalities in monoamine oxidase (MAO) levels are Associated with learning disabilities. We tested the two hypotheses with X VNTR polymorphisms in the linked MAOA gene were examined: (1) A variant of the MAOA gene was Play a role in either behavioral disorders associated with the syndrome or substance abuse What? (2) If so, what is the relationship between allele length and phenotypic effect? Is there a correlation? We examined two independent groups: 375 TS patients, Relatives and controls, and 280 substance abusers and controls. Conflict Gene variants were divided into four groups of increasing size. Both groups have MAOA gene and There was a significant association with the behavioral phenotype. And both are the longest conflicts Genes were associated with the greatest phenotypic effects. The strongest effect is on the diagnosis of drug dependence (P = 0.00003). VNTR alleles are associated with MAO-A activity Are in significant linkage disequilibrium with previously shown Fnu4HI. These results are short Different size alleles of the repeat polymorphism itself play a role in gene regulation In line with the possibility.   Age (Devor et al., 1994) versus platelet enzyme levels (Fowler et al., 1982), al Potential effects of calls, antidepressants, drugs, gender, laboratory techniques, diet, and other factors Because the use of genetic polymorphisms in the MAO gene is more reproducible than the enzyme level Can give some results. MAOA and VAOB gene cloning and sequencing, then Identification of related polymorphisms now allows such genetic studies.   Determine if a genetic variant in the MAOA gene is associated with TS or ADHD To achieve this, we provide a series of controls, TS probands and their relatives. Technology reported in DRD2, DβH, and DAT1 in TS (Comings et al. , 1996a) was used to examine the gene MAOA VNTR polymorphism (Hinds et al., 1992). Con A simple comparison of the frequencies of different alleles in trolls versus TS probands suggests that MAO The child may be associated only with a small number of specific actions that do not exist in all cases We can overlook these characteristics in 27 different behavioral variables because The possible role of the gene was tested.   We hypothesize that the length of the allele may itself be associated with a phenotypic effect. I became interested in the theory. The rationale for this is the simplest The sequence of the repeat results in the formation of Z-DNA in an amount that depends on the length of the repeat (Sch roth et al., 1992). The Z-DNA conformation releases the DNA helix, which This DNA helix exposes individual bases and interacts uniquely with nuclear proteins. (Rich et al., 1984). For these and other reasons, Z-DN A has been implicated in gene regulation (Comings, 1996a; 1996b). Mini satella And microsatellite polymorphisms affect gene functions involved in polygenic inheritance Play a role in the transformation in No. Because, when effective, monogenic disorders rather than polygenic disorders This is because it causes harm.   X-linked genes are unique to test this hypothesis and search for subtle effects To form a vehicle. Because, at least in men, each allele The heterozygous factor, which is thus present at the semijunction and is therefore confusing (this Which can be extensive when multiple alleles of different sizes are present). Repetition To test the hypothesis that length may be related to phenotypic effects, we examined VN TR alleles were divided into four groups of increasing length. This allows the present inventors to Indicates that shorter or longer alleles are preferentially associated with greater phenotypic effects. It is now possible to determine if they are linked.   Method. Subjects consisted of 57 controls and 299 TS probands (most of whom were multiple Affected individuals with associated behavioral impairment (Comings, 1990)) and TS Included were 90 affected and unaffected relatives of the odds. All subjects are non-Hispanic They were Caucasian (white) and over 90% were from Western Europe. TS Group controls include care and care for TS proband, City of Hope and others. With non-psychiatric disorders from a clinic in the United States, as well as the City of Hope Medical C It consisted of enter staff and non-special hospital staff. TS subjects and controls Have described in detail elsewhere (Comings, 1995b; Comings et al., 1996a; 1997b). .   Diagnostic Interview Sched for each TS control and TS proband or relative ule (Robins et al., 1981) or DSM-III-R (Diagnostic and Statistical Manual) of Mental Disorders, 1987) Required to fill out a questionnaire based on criteria . This has provided a structured review of a wide range of psychiatric syndromes. these Symptoms include 27 different behaviors (ADHD, substance abuse, depression, anxiety, school performance, stuttering, , And others). Quality used for these behavioral scores The question is elaborated elsewhere (Comings, 1995a; 1994a; 1994b; 1995b; Comin gs et al., 1996a; Robins et al., 1981; Comings, 1995c). Two behavior scores, ADHD Was used for evaluation. The first is called ADHD and is based on the DSM-III and DSM-III-R criteria. Based on the presence of at least half of a series of 22 ADHD variables. Second, ADHD-R is a DS Based on M-III-R diagnostic criteria. The three QTVs we have not used before are careless Was impulsive, and overactive. These produce cumulative ADHD scores. The Three sub-scores. QTV abbreviations are CD for behavioral disorder, ODD for rebellious behavioral disorder ( Comings, 1995a), and MDE of major depression (Comings, 1995c).   The rationale for examining co-morbid behavior is that certain genes are Earlier that it could be more strongly associated with certain co-morbidities present in TS Look (Comings et al., 1996a). This questionnaire covers the DSM-III-R or DSM-IV diagnosis It does not mean to provide, but rather to create QTV for different areas of action. Provide a highly structured way to achieve The advantage of continuous properties is that they Is to provide a greater range of severities than the diagnosis of For symptom evaluation The accuracy, usefulness, and sensitivity of the questionnaire-based approach depend on others (Gadow and S prafkin, 1994; Grayson and Carlson, 1991). Usage is shown by comparing it to the interviewer management of the same structured instrument. Examination of our questionnaire with hundreds of subjects will provide information obtained through personal interviews. It is shown to reflect accurately.   The second group of subjects was Loma Linda, Jerry L Pettis Veterans Admi of California. 120 non-his from the hospitalization Addiction Treatment Unit (ATU) of the nistration Hospital It consisted of panic Caucasian (white) men. Info since October 1994 All new permissions to the ATU to give unsuccessful consent may be Study of genetic factors in Japan supported by National Institute of Drug Abuse Migrated.   All ATU subjects were subjected to the Michigan Alcoholism Severity Test (Davis et al., 1987). The self-management questionnaire of 24 items was evaluated using the substance abuse (MAST-R), Includes Diagnostic Interview Schedule (DSM-III-R version (Robins et al., 1981)) Diagnostic Interview Schedule (DSM-III-R bar) John (Robins et al., 1981)), Addiction Severity Index Fifth Edditi for physician management Diagnose the presence of on (ASI) (Hodgins and Guebaly, 1992) Modified to evaluate the range of use indefinitely.   We utilized the section on Drug / Alcohol Use, ASI Legal Status. this The areas were as follows:   a) Use of certain drugs. In alcohol to assess the use of certain drugs Toxic use, heroin, other opiates / analgesics, barbiturates, other sedatives / Hypnotics / tranquilizers, cocaine, amphetamine, cannabis, hallucinogens and inhalants Asked about lifetime use (years).   b) Route of administration. For each of the above, the subject's route of administration, if relevant Asked. Options were oral, intranasal, smoking and IV injection. Continuous used Variable #IV drugs are by adding the total number of different drugs injected IV It was calculated. Variable IV drug use is zero if there is no IV drug use and one or more It was dichotomous to be less than 1 for the use of Drug IV above.   c) The problem. "How many times have you experienced alcohol DT?" "How many days have you had problems with alcohol in the last 30 days? About ".   d) Cost "How much did you spend on alcohol in the last 30 days? How much? "   e) Severity. Regarding the need for treatment, the severity rating based on the interviewer was 0 (no treatment needed). No) to 9 (the actions needed to intervene in life-threatening conditions) Range. About alcohol abuse. About substance abuse.   f) Legal status. Questions about various legal aspects of drug and alcohol abuse Asked again. "How many times have you been accused of drunk driving in your life?" Have you been arrested and charged with holding? "" How many of these charges have been convicted Did it become? "   g) Overall score. When the response is 0, the response can range from 0 to any number It was evaluated as “0” and “1” for an arbitrary number. About alcohol use These questions should be your total alcohol score, and these questions about drug use should be Totals for object scores.   Controls for the substance abuse group are independent of controls for TS patients. Erect. They consisted of two sets. First, there are 45 older men, San  Non-Hispanic Caucasus from the California State University of Bernardino He is a white student (average age 30.1). Has a significant problem of substance abuse Students were excluded based on the MAST-R test. The second set is the Minnesota Twin F The amily study consisted of twin male parents. These have twins 11 or 17 They are more comprehensive than college students It represents a more random set of socioeconomic and educational groups of the body. Con All trawls scored negative for the substance abuse variable, but How much is the price result not yet available in the two twin controls Or positive. But this is mainly a random cross section of the local state Thus, the inventors considered that the number of false negatives in this group was small.   The rationale for selecting VNTR polymorphisms in the MAOA gene is as follows: You. Shorter, especially as we examine the hypothesis that the length of the repetition may be associated with a phenotypic effect A tandem repeat polymorphism was selected. X-linked genes were selected. Because at least men Avoids the complexity of interpreting heterozygotes when is studied Because it is done. The MAOI gene was selected. Because it is X-chained You. The MAOA gene was selected. Because two different repetitive polymorphisms are related Because it is reported that We have identified the VNTR polymorphism (Hinds Et al., 1992). Because it is in the allele size (40 + bp) This gave a wider spread than the (CA) n repeat (16 bp).   This complex polymorphism is associated with both dinucleotide and VNTR repeat numbers. Immediately adjacent to an incompletely duplicated novel 23 bp VNTR motif with different alleles GT microsatellite. VNTR polymorphisms implicate the first exon of the MAOA gene Included in the 2.9 kb SalI-EcoRI fragment from phage 6.12 which contained ( Hinds et al., 1992). DNA was extracted from whole blood by standard procedures. PCR target DNA^{T M} (Mullis et al., 1986). PCR^TM0.1 μM firefly to label the product Each primer or FAM amidite labeled with optical HEX (Applied Biosystems, Fost er City, CA, USA) primers were used in the reactions (Table 88). 2 μl 10-fold diluted PCR^TM The product is mixed with 2.5 μl deionized formamide and 0.5 μl ROX500 standard (Applied Bi osystems) and denatured at 92 ° C. for 2 minutes and applied to Applied Biosystems 37 3 Loaded on a 6% polyacrylamide gel in a DNA sequencer. Gel, 5 Electrophoresed at 1100V and stationary 30W for hours. Laser scan the gel, And analyzed using the ROX500 internal standard. Peak to Genotyper (version 1 . 1) (Applied Biosystems), coloring by base pair length Recognized based on fragments. Complete information about each sample, all Was printed from the gel file and the collected data was submitted for analysis.   To test the hypothesis that MAOA allele length may correlate with phenotypic effects Alleles were divided into four groups (see results). These are 1-4 (most Shortest to longest) to form the MAOA genotype variable. TS group for women Used only in. Only those groups that are homozygous for a given allele group , Included in the analysis.   We have used two rules for binning: a) Length range There must be enough groups to test the girth; and b) statistical power In order to maximize the number of subjects should be similar in each group. Therefore If there was a single peak of allele frequency, the split would be the shortest 1/3, medium One third of the order and the longest one third. However, the MAOA VTNR The distribution of progenic size was two peaks. Smaller for men only The small peak contains 32% of the allele and is 299-314 bp long in size. Reached. The larger peak is 68% of the size ranging from 323 to 338 bp in length. Alleles included. Because most of the alleles were at this peak, They split this as if there was a single peak (ie, Shorter, moderate, and larger alleles). The center of this peak is a single 334 bp group, which consists of 31% alleles that cannot be redifferentiated It is. The application of these rules consists of 32, 23, 31 and 14% of alleles. Less than 323 bp, 320 to 333 bp, 334b p and 335 bp or more.   It is not possible to use the split described by Hinds et al. (1992). Was. Because three of their five groups had very low allele frequencies It is. In fact, we are in one of these three minor groups There were no subjects.   Fnu4H1 polymorphism. Testing for this polymorphism has been described by Hotamisligil and Breakakefiel Based on the procedure of ed (1994). We have replaced their "-" with ours. The "1" alleles and their "+" were named our "2". their In the study, the + allele had higher MAOA activity.   For the Tourette syndrome group, using ANOVA, four different allele groups The relative size of each QTV was then tested. Using linear ANOVA, four oppositions We tested for a significant gradual increase in the mean across the gene group. SPSS (SPSS, Inc. Chicago, IL, USA) statistical package was used. For linear ANOVA, The subcommand polynomial was set to 1. Using MANOVA, one of the QTVs It was determined whether all variables were significant when tested simultaneously. Multivariable linear times Using inductive analysis as a second approach, one of the QTV Was determined to be significant if tested simultaneously. MAOA genotype dependent It was set as a number and 27 QTVs were assigned stepwise as independent variables.   Chi-square analysis shows that the group with the longest allele is the best for most of Was shown to have an average of Latentity in the frequency of alleles over 335 bp Regression was compared across four groups with progressively fewer TS symptoms: AD TS proband with HD, TS proband without ADHD, relatives with TS, and with TS No relatives.   For the substance abuse group, using MANOVA, four MAOA allele groups and two total There is a significant association between the summary variables alcohol score and drug score Or not. Using ANOVA, four groups of alleles were The average of the drug and drug scores was tested.   Using linear chi-square, three groups: control, drug abusers without behavior 335 bp across (without ATU) and drug abusers with behavior (with ATUC) The potential gradual increase in group frequency was tested above. The group without ATU has this conflict Increasing frequency in drug abusers due to co-morbidity of behaviors with different genes It clarified that it derives the possibility that it can be added. To help eliminate this For example, the frequency of alleles is higher for behavioral drug abusers than for Had to be at least 20% higher. This hypothesis is The frequency of their alleles increases progressively across these three groups That's why we used linear chi-square statistics.   Maximum percent change in drug-related variables to account for MAOA gene Subjects with less than 335 bp allele are scored as 1 to determine Subjects with a 335 bp or greater allele were scored 2 Regression analysis was performed. This was compared to the drug-dependent variables (control: 1, no ATU Scored 2; and with ATU scored 3). Because this was the chi-square variable most highly associated with the MAOA gene You.   result. MAOA VTNR polymorphism allele distribution (total number of alleles is 768 there were). Since this was a composite VTNR, alleles were even or singular in base pairs. Did not result in a clear pattern. The results, they are in the Genotyper program Thus, it is shown exactly as it is generated. Between 316 bp and 323 bp Alleles were not present. Therefore, less than 320 bp and more than 320 bp Two distinct major groups were generated. But if phenotypic effects can be related to size In order to be able to test the hypothesis, alleles of the larger 323-339 bp group The genes were divided into three subgroups. This subgroup contains the main peaks 320-333. bp, alleles with a major peak of 334 bp, and major genes Offspring consisted of 335 bp or longer alleles. 375 total in TS group There were 219 men and 156 women for the test subjects. Of the women, 88 Heterozygous. If these were excluded, this would mean that 36 was the control In one study, 287 subjects remained. In this final group, men vs women There were no significant differences in the frequency distribution of the four allele groups in the study.   The ANOVA results for each QTV for the TS group versus the four allele groups are shown in Table 88. You. The results for normal ANOVA are shown below the F ratio and P value. About linear ANOVA F ratio of F_TwoBelow the line, superscripts for those that are significant below 0.05^aIndicated by . The QTVs are ordered by the magnitude of the F ratio reduction in the F2 column. Set to 0.05 or less For groups with an average of 335 bp or more, as determined by the established Tukey test These allele groups when significantly smaller than are indicated by an asterisk. Except for stuttering, shopping, and panic (these gave the lowest F ratios) For those 24 subjects with an average of 35 or more alleles for 24 QTVs, About it was the best.   MANOVA results for all 27 QTVs were sexual behavior (P = 0.012), learning problem (P = 0.023), gambling (P = 0.025), and mania (P = 0.025) were significant.   If all 27 QTVs were tested simultaneously in a stepwise multivariate regression analysis, Several elementary school problems (p = 0.012) and gambling (P = 0.038) were significant. r^TwoTo the value On the basis, the MAOA gene accounted for only 3.9% of these QTV variations.   Using の -squared analysis, percent of subjects with alleles greater than or equal to 335 bp In, TS probands with ADHD (24%, n = 129) do not have ADHD Relatives with TS (12.5%, n = 16), up to TS proband (20.0%, n = 50), And a non-TS relative (5.6%, n = 56) with a significant gradual decrease (P = 0.003).   Controls versus ATU subjects in the substance abuse group were compared. 160 in total For all controls, the distribution of the four allele groups was as follows: Less than 320 is 34.4%, 320-333 is 38.1%, and 334-335 is 21.3%. 6.3% for 335 or more. For 120 ATU subjects, the frequencies are as follows: Was 39.2% for less than 320, 18.3% for 320-333, and 2 for 334. 0.8%, 21.7% for 335 or more. These are significantly different, χ^Two= 22.1 7, P = 0.00006. The frequency of the group 235 bp or more Comparable in the role group, 8 for the San Bernardino group . 9% and 5.2% for twin parents (χ^Two= 0.744, P = 0. 38).   MANOVA for alcohol and drug scores are both MAOA genetic It showed a significant association with the offspring VNTR allele, which was determined by the drug score (P = 0. 001) is more significant than for the alcohol gene (P = 0.012) (Table 89). N of 257 is 160 controls + 1 in total Less than 20 ATU or 280. Because only 97 ATU subjects , ASI was completed. In contrast, all 120 are alcohol and And / or DIS for confirmation of drug dependent DSM diagnosis completed.   Table 90 shows the ANOVA for the two scores indicating the mean for each allele group. Shown in For the TS group, the highest mean was in the allele group of 335 bp or more. Was. For drug score, three other allele groups were 335 by Tukey's test. The results were significantly lower than those of the bp group.   The MAO gene can be used to determine if it is preferentially associated with a particular type of substance abuse. Of the variables related to the type of drug used, 14 were tested using chi-square analysis. Con ATU subjects without trolls vs. behavior (without ATU) vs. ATU subjects with behavior (with ATU) Are shown in Table 91. Drug use variables Since 14 molds were tested, they had a P less than 0.036 (0.05 / 14). Only is considered relevant for Bonferroni correction. Has a p less than 0.01 Only those are shown. The only exception is alcohol dependence. This is called drug dependence or drug Have only alcohol dependence compared to those with substance and alcohol dependence The frequency of 335 or more bp allele in the subject was hardly increased This is shown to illustrate the facts. In contrast, a drug-only variable has the highest value (χ^Two = 17.4, P = 0.00003).   The regression analysis of the diagnosis of alleles (<335 vs ≧ 335) versus drug dependence Given the result: r = 0.25, r^Two= 0.0625, T = 4.305, and P = 0.0001.   To test for potential linkage disequilibrium between the VNTR and the Fnu4H1 allele, The authors genotyped 273 women who were also genotyped for VNTR polymorphisms. We have limited the analysis to men. Because the results are more clear than women This is because the. Highly significant non-random association of alleles at the two polymorphisms Existed (χ^Two= 132.91, P <0.000001). <320V NTR alleles are less common Associated with the non-target Fnu4H1 allele, while the remaining three VNTRs Associated with progeny.   Based on a comparison of the data, the VNTR allele was split into <320bp and> 320bp Have Fnu4H1 2 allele ≒ <320 and Fnu4H1 1 allele ≒> 320 It is expected that the result should be similar to polymorphism. For the TS group, both There were 71 subjects genotyped by typology. Mania gave the most significant results Therefore (Table 88), this variable was used for comparison. Fnu4H1 has one allele The average for 53 subjects is 2.01 (standard deviation 2.17) and the two alleles Was 1.55 (standard deviation). Comparable figures for VNTR are> 320bp 1.94 (std 2.12), and 1.75 (std 1.9) for the <320 bp group. 8). The 16 ≧ 335 subjects had a 2.43 (standard deviation 2.42). Relatively few Therefore, any grouping was not significant. Hotamisligil and Breakfield Research (1994) found that the Fnu4H1 allele (our I allele) had a lower MAO A 335 VNTR alleles are the lowest Hypothetical MAOA activity.   Tourette's syndrome is uniquely studied for such studies. Because high Genetic in nature, and often a wide range of impact, aggression, emotion, and libido Because it is associated with excess and other behaviors. The results of the present invention show that the MAOA gene Of genes that play a modest role in the pathogenesis of a number of related behaviors in TS Suggest one.   MANOVA is the relationship between the MAOA allele and both alcohol and drug scores. High co-morbidity of these two forms of drug abuse, while showing significant association Rate exists. Separate drug addiction and alcoholism as shown in Table 91. Is the association with the drug much greater than the association with alcoholism when tested in Was.   Dominance in women is probably due in part to hormonal and environmental factors In contrast, X-linked genes can also be factors. Regression coefficient for TS group Using r^TwoThe decision was that for different QTVs, the MAOA gene was almost 2.5%, Or X-linked MAOA gene calculated for male dominance of TS, ADHD, or related disorders Not be responsible for any QTV variable deficiencies suggesting that . In contrast, the absence or presence of the ≧ 335 bp allele, R2 suggested that up to 6.2% of the variables could be attributed to the MAOA gene. This It may play a modest role in the male dominance of drug dependence.   We consider different lengths of microsatellite and minisatellite polymorphisms. Alleles can play a role in regulating the genes to which they relate Began to predict. Longer minisa with specific QTV in Tourette syndrome The telite allele association was modest, while QT, as shown in Table 89. There was a remarkable degree of equality in the trends across all of V. This is a coincidence Since the association could be random, we determined that all subjects and controls Consider determining whether these results can be replicated in physically separate groups. I got it. This group (the substance abuse group) had a longer MAOA VNTR than was observed in the TS group Alleles (especially the ≧ 335 bp allele) still showed a strong association. Two groups Pattern indicates the highest score for the ≧ 335 bp allele and the lowest size allele. Moderately high score for the gene (<320), and for the 334-335 bp allele Notably similar to intermediate scores.   Whether the ≧ 335 bp allele can be associated with higher or lower MAO-A activity In order to gain some insight into Fnu4H1 polymorphisms, we have also 273 of our men were genotyped. Linkage disequilibrium with VNTR allele Equilibrium was highly significant (P <0.000001). Less common Fnu4H1 vs. 2 Alleles are associated with the <320 VNTR group, while the more common I allele is 320-333 , 334, and> 335V were associated with the NTR group. Others have MAO-A activity with a low range of behavioral disorders And we found that the greatest phenotypic effect of the VNTR polymorphism Was observed to be associated with the ≧ 335 bp group, which indicates that this group Is suggested to be related to MAO-A activity. These results indicate that the Fnu4H1 1 allele If a subject with Fn is placed in a subgroup based on VNTR polymorphism, Suggests that the subject has a ≧ 335 bp allele driving the result of u4H11 You. The final proof of these suggestions is to test for serum or fibroblast MAO-A activity Discovery requires the study of VNTR alleles in subjects The reason that the u4H1 polymorphism is associated with a difference in MAO-A activity is that one allele is ≧ 335 VN It is consistent with the possibility that the question is in linkage disequilibrium with the TR allele, and <320 alleles (associated with high MAO-A activity) versus ≧ 335 bp alleles (lowest M The large difference in the number of repeats between AO-A activity and Plays a role in the regulation of genes.   This correlation with the size of the repeated allele indicates that the minisatellites themselves Consistent with a possible role in regulation. However, an unidentified part This proves the hypothesis, because a chain imbalance with another such as rank can still occur. Clearly not. Studies on expression vectors and longer alleles Possible interaction with a transcription factor needs to prove the case for the MAOA gene is there.   The results for the TS group show the efficacy of the relatively low-scale MAOA gene in the range of behavior. Fruit. Four variables were significant in MANOVA and two were significant in multivariate regression analysis And 12 out of 27 are significant in linear ANOVA, but some are complete If Bonferroni correction is applied to the ANOVA result, it is 0.05 / 27 or 0.0018 It may be aimed at nothing. But this is exactly the issue. You That is, in different actions, despite the large literature involved in MAO, When tested at the genetic polymorphism level, the MAOA gene has a broad range of behavioral variables. Seems to make only a moderate correlation to. The effect is more in drug abuse As calculated herein by the MAOA allele, whereas potent The proportion of variables was still modest. Replication is an important aspect of related research, and These results were found in two completely different sets of subjects. this Find that many genes are involved in various behaviors, each with small effects Consistent with the concept of polygenic inheritance: and minisatellite polymorphisms themselves are polygenic Played a role in providing basic functional allelic variants for inheritance Is consistent with the hypothesis that                                 Example 30     Hypothetical Examples Related to Amino Acid Therapy and Premenstrual Ataxia (PMDD)   Premenstrual disorder (PMDD) is a premenstrual disorder that occurs periodically during most of the menstrual cycle Minute disability. In the DSM-IV category of “Depressive disorder unless otherwise specified” Included below. However, a number of factors (biological and cognitive studies, treatment response) And separate PMDD from other mood disorders (Yonkers, 1997).   Despite the predictability of luteal phase manifestations, the etiology of this disorder has not been established. No. Theories about hormonal and vitamin deficiencies are related to PMS, and PMD It may or may not be related to D. Nevertheless, progesterone, d Strogen, prostaglandin, insulin, vitamin B₆Or thyroid hormone Absolute or relative deficiency of Mont (Severino and Moline, 1989; Rickerl et al., 199 0; Bancroft and Rennie, 1993) have either PMS or PMDD Has not been established in any patient group. Similarly, thyroid against thyroid stimulating hormone Functional hormonal tests such as glandular releasing hormone response and glucose tolerance test results Studies are not abnormal in patients with PMDD (Casper et al., 1989; Girdler et al., 1 995; Haslkett et al., 1984; Roy-Byrne et al., 1987).   Hypothesis that premenstrual symptoms are induced by withdrawal of endogenous opiates In patients with symptoms and controls, some groups Was evaluated for the final level. In a study involving women who had previously reported premenstrual symptoms Giannini et al. Found a decrease in β-endorphin during the luteal phase of the cycle ( Giannini et al., 1984); however, there was no control group in this study. And also Nevertheless, four other studies found that patients with symptoms compared to controls Lower luteal β-endorphin levels (Tulenheimo et al., 198 7; Facchinetti et al., 1987; Chuong et al., 1985; and Gianini et al., 1990). The above research One is finding lower levels in the follicular as well as luteal phase (Tulenhei mo et al., 1987), and in further studies, β-endorphin levels It was lower in women with symptoms during the period (Chuong et al., 1994). In particular, Only two of the studies meet the severity criteria for diagnosing PMDD? May or may not, include pre-determined population Was. Differences in the patient population (small sample population or a combination of the two) Not find differences between PMDD patients and controls at any stage In a recent study (Bloch et al., 1996), it could be the basis for different conclusions. I However, in this study, β-endorphin levels were lower in pre-menstrual periods in both groups. For a while. Changes in portal venous blood levels of beta-endorphin during the menstrual cycle Also found in primates, the differences are most pronounced during the perovulatory period. (Wehrenberg et al., 1982).   Fluctuations in β-endorphin, which are markedly reduced during the menstrual cycle, are Can enhance adrenergic action in sex, and adrenergic receptors Could explain the results of studies on ter-binding. Halbreich et al. (Holbreich et al., 1993) Imidazoline receptor in women with premenstrual symptoms during the early luteal phase Ter bond was found. Adrenaline as outlined by Grunhaus et al. (1990) Alterations in phosphorylated receptor binding are also associated with MDD and panic disorder However, the direction of the change (increase vs. decrease in affinity) depends on the platelet preparation used in the assay. Depends on product and ligand.   In addition, endorphin and estrogen levels have been shown to vary I have. During postpartum and during premenstrual periods, both levels change rapidly and substantially (Ha lbreich and Endicott, 1981), and others, drug antagonists reduce PMS symptoms Showed a little.   Halbrech and colleagues found that during women with discomfort premenstrual symptoms, A decrease in gamma aminobutyric acid (GABA) levels was found (Holbreich et al., 1996). Low plasma GABA levels were also found in shelters with MDD (Petty et al., 1992 ), However, it is not known how this relates to the above findings.   Theories in the pathogenesis of PMS are almost exclusively estrogen, progesterone Or focused on prolactin secretion. By contrast, in the mid 80's, Labrum (1983) states that the symptoms occurring in PMS are brain level or seroto Shared, including abnormal fluctuations in nin, GABA, and correlated neuroendocrine processes It was first proposed to have an etiological basis. Estrogen feedback is Can be a factor in excessive fluctuations in serotonin.   For serotonin, whole blood, platelet 5-HT uptake, and neuroembryonic challenge In women with both PMS and PMDD, including measurement of serotonin in di A number of different approaches have been used to evaluate leverage systems. Low Primates suggest that serotonin is associated with changes in sleep, appetite, and irritability Rankin (1992) has severe premenstrual nervous anxiety based on class and other ratings Females are tested for whole blood serotonin and compared to asymptomatic controls Have found that symptomatic women have lower levels of serotonin. all Not all groups (Mahngren et al., 1987; Rojansky et al., 1991), but some The investigators (Ashby et al., 1988; Taylor et al., 1984; Ashby et al., 1990) reported luteal platelet 5-HT Uptake is reduced in women with PMS or PMDD compared to controls I found to do. The imipramine binding site is also in the early luteal phase (Rojansky et al., 1991) or during both phases of the cycle (Steege et al., 1992) In comparison, it was shown to be reduced in women specifically assessed for PMDD . In the latter study, statistically significant differences were obtained only during the follicular phase.   Administration of tryptophan to women with PMDD is weak during both phases of the menstrual cycle. Produce a long hormone response and a cortisol response (Bancroft et al., 1991), and This suggests a difference in properties between PMDD patients and controls. But the same two groups In prolactin response to tryptophan in It becomes weaker (Bancroft et al., 1991). On the other hand, 5-HT_1AThe partial agonist buspirone, When administered to PMDD patients and healthy controls during the follicular phase, Response (Yotham, 1993). Weak prolactin for phenfuramine administration Response data are available in well-characterized PMDD analyte controls. Differences between group found library response (FitzGerald et al., 1996) Not mixed with another group (Bancroft and Cook, 1995). Most Ultimately, the depletion of the serotonin precursor tryptophan is less than in asymptomatic women. Significantly increased premenstrual symptoms during both luteal and follicular phases in PMDD patients. (Menkas et al., 1994).   Numerous recent studies have identified certain psychotropic drugs for the removal of PMDD (clonipramine ( Sunblan et al., 1993), fluoxetine (Stone et al., 1991; Wood et al., 1992; Steiner) 1995; Brandenberg et al .; Pearlstein and Stone, 1994), bupropion (Pee arlstein et al., 1995), paroxetine (Eriksson et al., 1995; Yonkers et al., 1996a), Maprotiline (Eriksson et al., 1995), Sertraline (Yonkers et al., 1996b), Nef Axodon (Girdler et al., 1995), and fenfluramine (Brzezinski et al., 199). 0) (including antidepressants).   One, or possibly two more individual neurotransmissions by the inventors A single drug with only a limited effect on a substance may be Hormonal changes during the post-menstrual and post-menstrual period It is expected to be insufficient to overcome. In addition, the above biological evidence has been determined. Does not imply any single, neurobiological system, but Changes in binding, GABA levels, and various assays of the 5-HT system indicate that PMDD Suggests a neurobiological abnormality associated with the disease. Changes in these markers It is also found in unipolar MDDs. To date, enkephalinase in PMDD No studies have reported positive effects of inhibitors. In fact, Trexan^R(Dup ont, Delaware) have been used by the present inventors to Decrease rather than enhance PMDD, as opposed to what it does in research It is shown.   This is based on the latest findings by Figuerola et al. (DeLourdes-Figuerola et al., 1997). Combined with an increase in plasma ME at day 22 in the menstrual migraine group In norepinephrine (NE) levels in cells and crystals, as well as during pain Plasma ME, showed an increase in NE. The authors found that in plasma ME and Changes in adrenal function occurred not only during pain but also during mid-luteal phase And concluded.   We intended amino acid treatment to benefit patients with PMDD . In particular, a number of alcohols utilizing the compositions shown in Table 11 for this obstacle Studies achieved in patients with fulminant disease include irritability, tension, chest pain, headache, and depression. Representative PMS symptoms including depression were significantly reduced. The specific examples used are listed in Table 11. PMX outlined^TMSpecific to the formulation.   Double-blind placebo control study outpatients in PMDD clinic in Dallas, Texas Track in. Study a total of 100 patients. PMDD scale is Developed by and provided to all 100 patients. The scale can be any Medication (placebo or PXM^TM) Will be scored before receiving it. This study , At least three cycles are minimized for incorporation into the study. patient Must be a child of childbearing age and not pregnant . Comparisons were obtained between the two groups, and statistical analysis was conducted under the guidance of Robert Wood. Originally, University of Texas Health Sciences Center Department of Computing  Performed by Resource. Only pathological PMDD candidates are assessed according to DSM-IV criteria. Value. Then placebo or PXM for each patient for 3 months^TMIs administered. Further Next, each patient is genotyped using the MAA technique proposed in the present invention. So Therefore, at least a total of 29 genes are evaluated.   Carriers of the DRD2 A1 allele and other RDS-related pairs disclosed herein The progenitor is PXM^TMRespond well and have the most difficult time under placebo Was expected to do. The genotyping of an individual is based on specific targeted treatment outcomes. It was further expected to provide further information for estimation.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 48/00 A61P 3/04 A61P 3/04 25/00 25/00 25/18 25/18 25/20 25/20 25/24 25/24 25/28 25/28 25/30 25/30 43/00 43/00 111 111 A61K 37/02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG , KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (71) Applicant City of Hope National Medical Center California, USA 91010-0269, Duarte, East Duarte Road 1500 (72) Inventor Bloom, Kenneth USA Texas 78258, San Antonio, Lost Stone 1211 (72) Inventor Cummings, David E. United States Country California 91010, Duarte, Crestview Court 59 (72) inventor Ivy, John El. United States, Texas 78759, Oh Sutin, Sky Flower Drive 10405

Claims (1)

[Claims] 1. A composition for the treatment of RDS behavior in a subject, comprising: a) at least one substance that inhibits the enzymatic destruction of a neuropeptide opiate, wherein the amino acid, peptide, and structural analog or derivative thereof. An opiate destruction inhibitory amount of a substance selected from the group consisting of: b) dopamine precursors L-Tyr, L-Phe, and L-dopa; serotonin precursors L-Trp and 5-hydroxytryptophan; And the amount of at least one neurotransmitter precursor selected from the group consisting of L-glutamine, L-glutamic acid, and L-glutamate, which is a precursor of γ-aminobutyric acid (GABA), to promote neurotransmitter synthesis; and c) A tryptophan concentration-enhancing amount of chromium picolinate or chromium nicotinate, consisting essentially of the substance and the neurotransmitter precursor and the The composition wherein the amount of the chromium compound is effective to reduce RDS behavior in the subject. 2. A composition for the prevention or treatment of undesired weight gain in a subject, comprising: a) at least one substance that inhibits the enzymatic destruction of a neuropeptide opiate, comprising amino acids, peptides, and the like. B) a dopamine precursor L-Tyr, L-Phe and L-dopa, a serotonin precursor L-Trp and 5-hydroxytryptophan and gamma-aminobutyric acid (GABA) precursor L-glutamine, L-glutamic acid, and promotion of neurotransmitter synthesis of at least one neurotransmitter precursor selected from the group consisting of L-glutamate And c) a tryptophan concentration enhancing amount of chromium picolinate or chromium nicotinate; A composition wherein the amount of the neurotransmitter precursor and the chromium compound is effective to prevent or reduce unwanted weight gain in the subject. 3. A composition for the treatment of attention deficit disorder, comprising: a) at least one substance that inhibits the enzymatic destruction of a neuropeptide opiate, comprising amino acids, peptides, and their structural analogues or derivatives. An opiate destruction-inhibiting amount of a substance selected from the group; b) L-Tyr, L-Phe, and L-dopa which are dopamine precursors, L-Trp and 5-hydroxytryptophan which are serotonin precursors, and γ An amount of at least one neurotransmitter precursor selected from the group consisting of aminobutyric acid (GABA) precursors L-glutamine, L-glutamic acid and L-glutamate, which promotes neurotransmitter synthesis; c) chromium picolinate And a tryptophan concentration-enhancing amount of a mineral compound selected from the group consisting of chromium nicotinate; and d) the group consisting of Rhodila or fusazine A neurotransmitter synthesis-promoting amount of at least one neurotransmitter synthesis promoter selected from the group consisting of: the substance, the neurotransmitter precursor, the mineral compound, and the neurotransmitter synthesis promoter. A composition wherein the amount is selected such that the inhibitory component is effective to reduce attention deficit disorder, attention handling, or memory. 4. Subjects with an RDS selected from the group consisting essentially of SUD, obesity, smoking, Tourette's syndrome, ADHD, schizophrenia / avoidance behavior, aggression, post-traumatic stress syndrome, PMS, or tobacco use The following: a) at least one substance that inhibits the enzymatic destruction of neuropeptide opiates, the amount of the substance inhibiting opiate destruction selected from the group consisting of amino acids, peptides, and structural analogs or derivatives thereof; b) dopamine precursors L-Tyr, L-Phe and L-dopa, serotonin precursors L-Trp and 5-hydroxytryptophan, and gamma aminobutyric acid (GABA) precursor L-glutamine; A neurotransmitter synthesis-promoting amount of at least one neurotransmitter precursor selected from the group consisting of L-glutamic acid and L-glutamate; and c) picoline Method of treating a subject by administering a composition comprising a tryptophan concentration enhancing amount of chromium or nicotinic acid chromium. 5. The administration is a daily dietary consumption comprising 32-10,000 mg DL-phenylalanine, 5-5,000 mg L-tryptophan, 3-30,000 mg L-glutamine, and the composition comprises 1-300 mg pyridoxal 5. The method of claim 4, further comprising 5'-phosphate. 6. 5. The method of claim 4, wherein said RDS behavior is obesity. 7. The method of claim 1 wherein the administration is a daily dietary consumption comprising 460 mg DL-phenylalanine, 25 mg L-tryptophan, 25 mg L-glutamine, and the composition further comprises 5 mg pyridoxal 5'-phosphate. 7. The method according to 6. 8. 7. The method of claim 6, wherein the subject has a family history of drug dependence, wherein the family history indicates an improved probability of success. 9. 7. The method of claim 6, wherein said administering suppresses macrophagia. 10. 7. The method of claim 6, wherein said administering suppresses a desire. 11. D ₂ TaqI A1, B1, C1 or exon ^6-7 haplotype HTR2A-C allele homozygous OB-1875 homozygous for allele below 208BP dinucleotide repeat polymorphisms human chromosome 2 microsatellite polymorphism, 7. The method of claim 6, wherein the presence in the subject of at least one allele of the conjugation, APO-D-TaqI 2.2 or 2.7BP, or the OB gene D7S1875 allele indicates an improved probability of successful response. Method. 12. 7. The method of claim 6, wherein the administration comprises an effective amount of chromium nicotinate, and wherein the presence of the DRD2 A1 allele in the subject indicates an improved probability of a response. 13. 12. The method of claim 11, wherein said administering comprises an effective amount of chromium picolinate, and wherein the presence of a DRD2 A1 allele in said subject indicates an improved probability of a response. 14． 5. The method of claim 4, wherein said RDS behavior is tobacco use. 15. D1 (homozygous for Dde A1) D2 (TaqI A1) D4 (VNTR 2) D5 (BP range of dinucleotide 13 allele 135-159) DAT1 VNTR (10/10) DβH (TaqI BI allele) 15. The method of claim 14, wherein the presence of one allele in said subject indicates an improved probability of a successful response. 16. The RDS behavior further comprises autism, Tourette's syndrome, or ADHD, and the subject has D (Dde A homozygosity) D (Taq) D (VNTR) D (dinucleotide allele BP 5.) DAT VNTR (/) DβH (Taq B allele) having at least one allele of MAOA (X), and wherein the presence of at least one allele indicates an improved probability of successful response. The method described in. 17． 17. The method of claim 16, wherein said administering further comprises an effective amount of Rhodila or fuvadine. 18. The RDS behavior is pathological gambling, and the presence of at least one allele of D (Homozygous for Dde A) D (Taq A, B, C) in the subject is a successful response. 5. The method of claim 4, wherein said method exhibits improved probabilities. 19. The RDS behavior, pathological violence, fissile / avoidant (SAB), wherein aggression, anger, further hostile or post-traumatic stress disorder, and D (Taq A, B, C , exon ^-) 5. The method of claim 4, wherein the presence in the subject of at least one allele homozygous for the DAT (VNTR /) mNOSIa-BP allele or less indicates an improved probability of a successful response. 20. The RDS behavior is PMS, and _{DAT1 VNTR (10/10) D 2 TaqI} A1, B1, C1, exon ^6-7 haplotype, or DRD1, DRD2, DRD4, HTT, , HTR1A, TDO2, DβH, MAO, COMT 5. The method of claim 4, wherein the presence of at least one of the alleles from the GABRAB, GABRB3, PENk, ADRA2A or ADRA2C gene indicates an improved probability of a successful response. 21. 5. The method of claim 4, wherein said RDS behavior further comprises a substance abuse disorder. 22. 22. The method of claim 21, wherein the RDS behavior is a drug use disorder. 23. DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, HTT, HTR1A, TDO2, DβH, ADRA2A, ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, CRF, HTR2Aβ A method of determining a subject's genetic predisposition to at least one RDS behaviour, comprising detecting at least one allele from a group comprising the HTR2C, interferon gamma, CD8A, or PS1 gene. 24. The RDS behavior is mania, OCD, sexual behavior, sleep, elementary school behavior, gambling, learning, carelessness, ADHD, ADDR, urge, MDE, CD, irritability, phobia, schizophrenia, general anxiety, somatization 24. The method of claim 23, wherein the method is selected from the group comprising the use of: a drug, an IV drug, reading, ODD, tics, alcohol or tobacco. 25. 25. The method of claim 24, wherein said allele is a VNTR polymorphism of the MAOA gene. 26. 24. The method of claim 23, wherein said RDS behavior is schizophrenia or avoidance. 27. The allele, DRD ₂ gene A ₁ allele, DAT ₁ gene, are selected from the group comprising VNTR 10/10 allele or DβH gene B1 allele, The method of claim 26. 28. 24. The method of claim 23, wherein said RDS behavior is drug use. 29. 29. The method of claim 28, wherein the allele is an increased number of (AAT) _n triplet repeats in the CNR1 gene. 30. The RDS behavior may be obesity, anxiety, depression, psychosis, hostility, paranoid ideation, obsession, symptom total, systemic symptom index, novelty exploration, overall total behavior, nervousness, and habit. 24. The method of claim 23, wherein the method is selected from the group comprising conscientiousness. 31. 34. The method of claim 30, wherein said allele is selected from the group comprising an increased number of D7S1873, D7S1875, D7S514, or D7S680 dinucleotide repeats in the OB gene. 32. 32. The method of claim 31, wherein the number of D7S1875 dinucleotide repeats is greater than 225 bp in both copies of the CNR1 gene. 33. The allele is a D ₂ A1 allele of DRD2 gene A method according to claim 32. 34. The detecting step is due to the fact that D ₂ A1 allele of DRD2 gene, and the OB gene, to detect the alleles selected from the group comprising D7S1873, D7S1875, D7S514 number increased or D7S680 dinucleotide repeats, 31. The method of claim 30. 35. 35. The method of claim 34, wherein said determining is for obesity. 36. The RDS behavior includes Tourette's syndrome, manic syndrome, rebellious behavior, sexual behavior, ADH DR, schizophrenia, ADHD, tic, major depression, behavior, stuttering, obsessive-compulsive, somatization, alcohol abuse, learning, and sleep disorders 24. The method of claim 23, wherein the method is selected from a group. 37. The allele is a D ₂ A ₁ allele of DRD2 gene A method according to claim 36. 38. The RDS behavior includes Tourette's syndrome, ADHD, smoking, learning, primary school behavior, ADHD-R, rebellious behavior, tics, mania, alcohol, reading, substance abuse, sleep, stuttering, obsessive-compulsive, somatic, and major depression. 24. The method of claim 23, wherein the method is selected from the group comprising: 39. 39. The method of claim 38, wherein said allele is the Taq1A1 allele of the DβH gene. 40. 39. The method of claim 38, wherein the RDS is Tourette's syndrome and the determining is by detecting an increased number of Taq B1 and Taq A1 alleles of the DβH gene. 41. Wherein the RDS behavior is from the group comprising Tourette's syndrome, autism, somatization, alcohol, ADHD-R, major depression, panic, obsessive-compulsive, general anxiety, mania, rebellious behavior, sexual behavior, reading, and ADHD. 24. The method of claim 23, wherein the method is selected. 42. 42. The method of claim 41, wherein said Tourette's syndrome is by detecting an increase in the number of at least one 10 allele of the DAT1 gene. 43. Wherein said RDS behavior is from the group comprising AVHD, stuttering, ADHD-R, rebellious behavior, tics, behavior, obsessive-compulsive, mania, alcoholic, general anxiety, depression, schizophrenia, sleep, sexual behavior, drugs, and major depression. 24. The method of claim 23, wherein the method is selected. 44. The RDS behavior, 10 alleles of DAT1 gene, by detecting an increase in the number of at least one allele selected from the group comprising D ₂ A1 allele of Taq A1 allele or DRD2 gene, the DβH gene 44. The method of claim 43, wherein the method is determined. 45. Said RDS behavior is selected from the group relating to alcohol, smoking, compulsive eating, tics, gambling, drugs, reading, shopping, rebellious behavior, major depressive episodes, schizophrenia, ADHD, behavioral disorders, obsessive-compulsive, and mania 24. The method of claim 23. 46. 46. The method of claim 45, wherein said determining is by detecting homozygosity for the DdeI allele of the DRD1 gene. 47. 24. The method of claim 23, wherein the RDS behavior is selected from the group comprising rebellious behavior, behavioral disorders, eating, smoking, gambling, ADHD, obsessive-compulsive, mania, and alcohol. 48. 48. The method of claim 47, comprising detecting the TaqIA1 and TaqIA2 alleles of the DRD2 gene. 49. 24. The method of claim 23, wherein said RDS behavior is selected from the group comprising Tourette's syndrome, smoking, and gambling. 50. 50. The method of claim 49, wherein said determining is by detecting an 11 or 22 genotype of the DRD1 gene. 51. 51. The method of claim 50, wherein said determining is by detecting two copies per genome of the DdeI allele of the DRD1 gene. 52. 24. The method of claim 23, wherein the RDS behavior is selected from the group comprising rebellious behavior, behavioral disorders, compulsive eating, smoking, gambling, ADHD, mania, stuttering, obsessive-compulsive, and schizophrenic behavior. 53. 53. The method of claim 52, wherein said determining is by detecting an increase in the number of 11 genotypes of the DRD1 gene. 54. Said determining is by detecting the DRD2 A1 allele, and said RDS behavior is gambling, smoking, compulsive eating, rebellious behavior, major depressive episode, ADHD, behavioral disorder, schizophrenia, compulsive, 24. The method of claim 23, wherein the method is selected from the group comprising mania, and alcohol. 55. 55. The method of claim 54, wherein said determining is by detecting two copies per genome of the DdeI allele of the DRD1 gene. 56. 24. The method of claim 23, wherein the RDS behavior is selected from the group including alcohol, smoking, compulsive eating, ticks, gambling, drugs, reading, shopping, gambling, and elementary school behavior issues. 57. 57. The method of claim 56, wherein said determining is by detecting an 11 or 22 genotype of the DRD11 gene. 58. 24. The method of claim 23, wherein said RDS behavior is Tourette's syndrome. 59. 59. The method of claim 58, wherein said determining is by detecting a G → A polymorphism in intron 6 of the tryptophan 2,3 dioxygenase gene. 60. 24. The method of claim 23, wherein the RDS behavior is selected from the group comprising ADHD, alcohol dependence, drug dependence, morbid betting. 61. 61. The method of claim 60, wherein said determining is by detecting a G → T polymorphism in intron 6 of the tryptophan 2,3 dioxygenase gene. 62. 24. The method of claim 23, wherein said RDS behavior is selected from the group comprising ADHD, alcohol dependence, drug dependence, morbid betting, and depression. 63. 63. The method of claim 62, wherein said determining is by detecting a DGGE polymorphism in intron 6 of the tryptophan 2,3 dioxygenase gene. 64. 24. The method of claim 23, wherein said RDS behavior is drug use. 65. 65. The method of claim 64, wherein said determining is by detecting a base pair allele (<181 bp) polymorphism that is less of an ADRA2C dinucleotide repeat polymorphism. 66. 24. The method of claim 23, wherein the RDS behavior is alcohol use. 67. 67. The method of claim 66, wherein said determining is by detecting an allele of two more base pair alleles (183 bp or more) of the ADRA2C dinucleotide repeat polymorphism. 68. 24. The method of claim 23, wherein said RDS behavior is selected from the group comprising alcohol and tobacco use. 69. 69. The method of claim 68, wherein said determining is by detecting two homozygous alleles for a presenilin-1 (PS1) polymorphism. 70. 69. The method of claim 68, wherein said determining is by detecting two homozygous alleles of greater than 80 bp of the CA dinucleotide repeat polymorphism of the PENK gene. 71. 24. The method of claim 23, wherein said RDS behavior is selected from the group comprising CD, ODD, or hypersensitivity. 72. 72. The method of claim 71, wherein said determining is by detecting the presence of a short GGC allele of the AR gene. 73. 24. The method of claim 23, wherein the determining is for alcohol dependence, cocaine addiction, or type B behavior in an RDS proband, and comprising detecting the presence of a DRD2 allele associated with the predisposition in the patient. the method of. 74. DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, HTT, HTR1A, TDO2, DβH, ADRA2A, ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, CRF, HTR1Dβ A method for determining a genetic predisposition to a polygenic trait comprising detecting at least one allele from a group comprising the HTR2C, interferon gamma, CD8A, or PS1 gene. 75. The genetic predisposition is a lack of susceptibility to ADHD, and the determining comprises DRD1, DRD2, DRD5, DAT1, HTT, HTR1A, TDO2, DBH, ADRA2A, ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3 75. The method of claim 74, comprising detecting at least one allele associated with the, CNR1, CNRA4, NMDAR1, PENK, AR, or CRF gene gene. 75. Wherein said genetic predisposition is lack of susceptibility to ADHD, and said determining comprises detecting at least one allele associated with the DRD3, DRD4, HTR1Dβ, HTR2A, HTR2C, interferon γ, CD8A or PS1 gene. 75. The method of claim 74, comprising. 76. The genetic predisposition is OOD, and the determining comprises DRD1, DRD2, DRD3, DAT1, HTT, HTR1A, HTR2A, HTR2C, DβH, ADRA2A, ADRA2C, MAOA, COMT, G ABRA3, GABRB3, CNR1, 75. The method of claim 74, comprising detecting at least one allele associated with the CHRNA4, NMDAR1, PENK, AR, or CD8A gene. 77. The genetic predisposition is tic, and the determining is at least one allele associated with a DRD1, DRD5, HTR1A, HTR1Dβ, HTR2C, TDO2, DβH, ADR2C, COMT, GABRA3, GABRB3, CNR1, or CHRNA4 gene. 75. The method of claim 74, comprising detecting the gene. 78. Wherein said genetic predisposition is LD, and said determining comprises detecting at least one allele associated with the DRD1, HTR2C, TDO2, DβH, ADR2A, ADR2C, MAOA, CNR1 or CNRA4 gene. 75. The method according to claim 74. 79. 75. The method of claim 74, wherein the genetic predisposition is elevated LDL levels, and wherein the determining comprises detecting at least one allele associated with the HTT, OXYR, DRD2, or PS1 gene. Method. 80. 75. The method of claim 74, wherein said genetic predisposition is elevated cholesterol levels, and wherein said determining comprises detecting at least one allele associated with an HTT, OXYR, DRD2, or PS1 gene. . 81. 75. The method of claim 74, wherein said genetic predisposition is longevity, and said determining comprises detecting at least one allele associated with a PS1, OXYR or APOE gene. 82. A method for developing a diagnostic polygenic assay comprising the following steps: a) identifying the trait to be studied; b) creating a scale to measure the severity of the trait to be studied C) selecting at least one candidate gene that can contribute to the trait; d) identifying at least one polymorphism associated with the candidate gene; e) conflicting the measure with the polymorphism. Correlating the pattern of the gene; f) comparing the pattern of the allele to the correlation of the candidate gene for the trait; and g) determining the pattern of the allele positively associated with the trait. In addition, forming a polygenic assay that is diagnostic. 83. The candidate gene is DRD1, DRD2, DRD5, DAT1, HTT, HTR1A, TDO2, DβH, ADRA2A, ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR, CRF, DRD3, 83. The method of claim 82, comprising the DRD4, HTR1D [beta], HTR2A, HTR2C, interferon gamma, CD8A, or PS1 gene. 84. 83. The polygenic trait comprises ADHD, lack of ADHD, ODD, CD, LD, tic, substance abuse / dependence, smoking, osteoarthritis, elevated cholesterol levels, elevated LDL levels, or longevity. The method described in. 85. The polygenic assay for ADHD is DRD1, DRD2, DRD5, DAT1, HTT, HTR1A, TDO2, DβH, ADRA2A, ADRA2C, NET, MAOA, COMT, GABRA3, GABRB3, CNR1, CNRA4, NMDAR1, PENK, AR 85. The method of claim 84, comprising detecting at least one allele associated with the CRF gene. 86. The method of claim 84, wherein the polygenic assay for the absence of ADHD comprises detecting at least one allele associated with a DRD3, DRD4, HTR1Dβ, HTR2A, HTR2C, interferon gamma, CD8A, or PS1 gene. the method of. 87. The polygenic assay for the ODD is DRD1, DRD2, DRD3, DAT1, HTT, HTR1A, HTR2A, HTR2C, DβH, ADRA2A, ADRA2C, MAOA, COMT, GABRA3, GABRB3, CNRLCHNRA4, NMDAR1, PENK, AR, or CD8A gene. 85. The method of claim 84, comprising detecting at least one allele associated with 88. Detecting the at least one allele associated with the DRD1, DRD5, HTR1A, HTR1Dβ, HTR2C, TDO2, DβH, ADRA2C, COMT, GABRA3, GABRB3, CNR1, or CHNRA4 gene for the tic. 85. The method of claim 84, comprising. 89. The method of claim 84, wherein the polygenic assay for the LD comprises detecting at least one allele associated with the DRD1, HTR2C, TDO2, DβH, ADR 2A, ADR2C, MAOA, CNR1 or CNRA4 gene. Method. 90. 85. The method of claim 84, wherein said polygenic assay for elevated LDL levels comprises detecting at least one allele associated with an HTT, OXYR, DRD2, or PS1 gene. 91. 90. The method of claim 84, wherein said polygenic assay for said longevity comprises detecting at least one allele associated with a PS1, OXYR or APOE gene. 92. The polygenic assay for osteoarthritis comprises: 85. The method of claim 84, further comprising detecting at least one allele associated with the gene. 93. A composition for the treatment of RDS behavior in a subject, comprising: a) at least one substance that inhibits enzymatic destruction of a neuropeptide opiate, the amino acid, the peptide, and the structural analog or derivative thereof. An opiate destruction inhibiting amount of a substance selected from the group consisting of: b) a substance releasing an enkephalinase that releases neuronal endorphin or enkephalin, wherein the substance is selected from the group consisting of polypeptides or amino acids; and c ) At least one compound that blocks the effect of an opiate at any of the δ, μ, κ, σ, or ε receptors, wherein said drug is selected from the group consisting of naropotone or a narcotic antagonist such as IC 1154 129; A composition consisting essentially of an opiate antagonist amount of Wherein the amount of the substance and the neurotransmitter precursor and the chromium compound and the opiate antagonist is effective to reduce RDS behavior in the subject.