HUMAN MUTATION 28(12), 1156^1170, 2007 REVIEW ARTICLE Chasing Genes for Mood Disorders and Schizophrenia in Genetically Isolated Populations Tine Venken1,2 and Jurgen Del-Favero1,2 1 Applied Molecular Genomics Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium; 2University of Antwerp, Antwerpen, Belgium Communicated by Michael Dean Major affective disorders and schizophrenia are among the most common brain diseases worldwide and their predisposition is influenced by a complex interaction of genetic and environmental factors. So far, traditional linkage mapping studies for these complex disorders have not achieved the same success as the positional cloning of genes for Mendelian diseases. The struggle to identify susceptibility genes for complex disorders has stimulated the development of alternative approaches, including studies in genetically isolated populations. Since isolated populations are likely to have both a reduced number of genetic vulnerability factors and environmental background and are therefore considered to be more homogeneous compared to outbred populations, the use of isolated populations in genetic studies is expected to improve the chance of finding susceptibility loci and genes. Here we review the role of isolated populations, based on linkage and association studies, in the identification of susceptibility r 2007 Wiley-Liss, Inc. genes for bipolar disorder and schizophrenia. Hum Mutat 28(12), 1156–1170, 2007. KEY WORDS: complex genetics; isolated population; association studies; linkage analysis; bipolar disorder; schizophrenia INTRODUCTION Complex Genetics Hereditary diseases can be divided into three categories: genomic disorders, monogenetic disorders, and multifactorial or complex disorders. Genomic disorders include deletions, insertions, duplications, inversions, and translocations. Monogenic disorders are rare disorders that can be subdivided into disorders with a simple Mendelian mode of inheritance and disorders with a less clear pattern of inheritance due to imprinting, mitochondrial inheritance, phenocopies, genetic heterogeneity, variable clinical expression, age at onset, and incomplete penetrance. These complicating factors are also characteristic of complex disorders. Furthermore, the predisposition of complex disorders is determined by a complex interaction of multiple genetic and environmental factors. Therefore, the exact patterns of transmission, the specific number of susceptibility loci, the recurrence risk ratio attributable to each locus, and the degree of the interaction between loci in complex disorders are unknown. Combined with the largely unknown pathophysiology of complex disorders, positional cloning was the method of choice in the past decade to identify disease-linked chromosomal regions. However, this approach proved to be less efficient for complex disorders as compared to the positional cloning of genes for Mendelian diseases [Dean, 2003]. MAJOR AFFECTIVE DISORDERS AND SCHIZOPHRENIA The spectrum of major affective disorders and schizophrenia (SZ) are among the most common brain diseases worldwide, r 2007 WILEY-LISS, INC. constituting a major public health problem with a high rate of morbidity and mortality [Muller-Oerlinghausen et al., 2002]. Although there is evidence of clinical overlap between different psychiatric disorders, traditionally psychiatrists distinguish subtypes based on clinical signs and symptoms, which is based on the distinction made by Kraeplin between the affective disorders, such as bipolar (BP) and unipolar (UP) disorder, and SZ as different clinical entities. These entities are categorized in classification systems such as the Diagnostic and Statistical Manual of Mental Diseases (DSM). BP disorder or manic depression (MIM] 125480) is, with a lifetime prevalence of 0.5 to 1.5%, equally frequent in males and females, a chronic psychiatric disorder, and characterized by disturbances in mood, ranging from mania to a severe state of depression, often accompanied by psychotic features, including delusions and/or hallucinations [Ketter et al., 2004] and cognitive Received 22 January 2007; accepted revised manuscript 24 May 2007. Correspondence to: Prof. Dr. Ir. Jurgen Del-Favero PhD, Applied Molecular Genomics Group,VIB - Department of Molecular Genetics, University of Antwerp - Campus CDE, Parking P4, Building V, Room 1.14, Universiteitsplein 1, BE-2610 Antwerpen, Belgium. E-mail: jurgen.delfavero@ua.ac.be Grant sponsors: InterUniversity Attraction Poles Program P5/19, Federal Science Policy O⁄ce; Fund for Scienti¢c Research Flanders (FWO); Special Research Fund of the University of Antwerp (Belgium). DOI 10.1002/humu.20582 Published online 20 July 2007 in Wiley InterScience (www.interscience. wiley.com). HUMAN MUTATION 28(12), 1156^1170, 2007 impairment [MacQueen et al., 2005]. A typical BP patient alternates a manic episode with one or more depressive episodes, but the latter is not necessary for diagnosis of BP disorder. Patients with BP disorder type I (BPI) suffer from severe phases of mania, while in case of type II (BPII) the manic episodes are less severe (called hypomania). On the other hand, patients with UP disorder (MIM] 608520) present only recurrent episodes of major depression. UP disorder is, with a mean lifetime prevalence of about 10%, more common than BP disorder, occurring twice as much in females compared to males. SZ (MIM] 181500) has a lifetime prevalence of 1%, equally frequent in males and females, and is characterized by positive symptoms, including delusions, hallucinations and disturbances in thoughts, and negative symptoms such as lack of motivation and poor social and occupational adjustment, as well as cognitive dysfunction. Although the etiology and pathophysiology of major affective disorders and SZ are still unknown, twin, adoption, and family studies supported for strong genetic determinants. These studies indicate that there is between 30 and 50% heritability for UP disorder, between 60 and 85% for BP disorder, and 80% for SZ and that relatives of probands have an increased risk for other psychiatric disorders among the spectrum [Shih et al., 2004; Smoller and Finn, 2003]. The exact pattern of transmission, however, is complex, likely involving both multiple genes and environmental factors. Furthermore, some patients suffer from schizoaffective (SA) disorder, which is characterized by both mood and psychotic features; therefore, SA disorder has overlapping clinical features of both BP disorder and SZ. Common clinical features for the different clinical entities, the existence of patients with SA disorder, the clustering of psychiatric disorders in families with an increased risk for relatives for other psychiatric disorders among the spectrum, as well as a twin study [Cardno et al., 2002] suggest an overlap between these disorders, clinically as well as biologically. Therefore, some genes might have relative specificity for either BP disorder or SZ, while other genes might confer risk across the spectrum of psychiatric disorders [Craddock et al., 2005]. Increasing Homogeneity in Complex Genetics The large efforts to identify susceptibility genes for complex disorders have stimulated the development of alternative approaches. Since genetic heterogeneity has been a major problem in complex genetics, researchers have tried to obtain increased homogeneity in their study samples to reduce complexity. In the case of BP disorder, for example, studies have been conducted in patients with an early age at onset, which is associated with increased severity, resistance to mood stabilizers, increased anxiety, poorer functioning, and increased risk of psychiatric hospitalization. Additionally, relatives of early-onset probands are more likely to develop affective disorders than relatives of late-onset probands. Therefore, genetic factors can play a greater role in early-onset forms than in late-onset forms and early-onset forms may thus be considered as a more homogeneous subgroup [Lin et al., 2005]. Other researchers have departed from the DSM-based clinical boundaries and studied patients with a specific common clinical feature such as psychosis, which is characteristic for SZ, SA disorder, and some severe cases of BP [Hamshere et al., 2005]. Additionally, the occurrence of psychotic features has been used as subphenotype for BP disorder to stratify the study sample for disease severity [Potash et al., 2003]. 1157 Recently, alternative phenotypic definitions have been developed that might be more closely related to biological systems (endophenotypes), such as sensory gating deficits or working memory dysfunction [Gottesman and Gould, 2003]. Isolated Populations Another approach to reduce underlying genetic complexity is the use of isolated populations. Isolated populations originated from a small number of founder couples. Throughout history, many populations, including isolated as well as outbred populations, undergo alternating periods of bottlenecks with rapid expansion of the population. These bottlenecks, invoked by, e.g., war, epidemics, or famine, are characterized by a reduction in population size followed by the survival and expansion of a small random subset of the original population. Due to increased inbreeding and genetic drift in isolates, certain alleles will be present more frequently in the population, while others are lost, increasing genetic homogeneity. Additionally, due to geographic, cultural, or religious barriers, isolated populations did not experience a large degree of admixture with surrounding populations for a number of generations, resulting in a relatively small gene pool (founder effect) [Peltonen et al., 2000]. Monogenetic disease genes have earlier been mapped using isolated populations, in which individuals tend to share ancestral haplotypes derived from a handful of founders. Since a rare monogenetic disease is almost always caused by a single founder gene or mutation in an isolate, haplotype mapping has been successful in mapping rare disease genes, using only a few distantly-related affected individuals with a low density simple tandem repeat (STR)-map (10 cM density) [Houwen et al., 1994]. Despite the genetic and environmental complexities, geneticists have tried mapping genes for several complex diseases, using population isolates since they are likely to have both a reduced number of genetic vulnerability factors and environmental background and are therefore considered more homogeneous compared to outbred populations. Isolated populations have indeed already been used successfully to map genetic susceptibility factors in some complex disorders, such as type 2 diabetes [Grant et al., 2006; Horikawa et al., 2000] and stroke [Gretarsdottir et al., 2003]. Major Linkage and Association Findings in Bipolar Disorder and Schizophrenia The complex genetic etiology of BP disorder and SZ might explain the numerous linkage signals throughout the genome that have been reported by independent research groups over the years. Nevertheless, some genomic regions have gained consistent support from independent studies and/or large meta-analyses based on STR-based genome scans. These loci for SZ include chromosomes 1p13.3–q23.3, 2p12–q22.1, 6p24–p22, and 8p22–p21.1. On the other hand strong evidence exists for genomic regions related to BP disorder on chromosomes 9p22.3–p21.1, 10q11.21–q22.1, 12q21–q24, 14q24.1–q32.12, and 18. Regions for SZ and BP, as well as for SA disorder, have been identified on chromosomes 1q32–q42.1, 6q16–q27, 8q24, 13q12–q34, and 22q11–q22, suggesting that these loci harbor a susceptibility gene for these psychiatric disorders in general [Badner and Gershon, 2002; Craddock and Forty, 2006; Lewis et al., 2003; McQueen et al., 2005; Riley and Kendler, 2006; Segurado et al., 2003]. For some of these loci, putative susceptibility genes have been identified for BP disorder and/or SZ with significant evidence from studies conducted in isolated Human Mutation DOI 10.1002/humu 1158 HUMAN MUTATION 28(12), 1156^1170, 2007 TABLE 1. Susceptibility Loci Identi¢ed for BP Disorder and/or SZ With Signi¢cant Evidence in Isolated Populations Locus Disorder Supported by a meta-analysis Genea Locusb Evidence in isolated populations 1p13.3^q23.3 SZ1BP Lewis et al. [2003] NOS1AP 1q23.3 1q32^q42.1 5q23.2^q34 SZ1SA SZ1BP DISC1 1q42.1 Lewis et al. [2003] 6q16^q27 SZ1BP McQueen et al. [2005] QKI AHI1 6q26^q27 6q23.3 8p22^p11 10q11.21^q22.1 SZ SZ1BP Badner and Gershon [2002] Segurado et al. [2003] NRG1 GRID1 8p21^p12 10q22 12q21^q24 BP P2RX7 DAO TPH2 12q24 12q24 12q21.1 13q12^q34 SZ1BP Badner and Gershon [2002] DAOA 13q34 18 BP Segurado et al. [2003] Quebec Ashkenazi Jews Finland Several Central American isolates Portuguese islands Finland Northern Sweden Israeli Arabs Portuguese islands Iceland Ashkenazi Jews Israeli Arabs, Faroe Islands, Cuba Quebec Quebec Northern Sweden, Quebec Faroe Islands, Finland Quebec Micronesian islands Several Central American isolates Ashkenazi Jews Quebec a Gene symbols according to the HUGO ^ Human Genome Nomenclature Committee website (www.gene.ucl.ac.uk/nomenclature). Cytogenetic location of the gene according to NCBI (www.ncbi.nlm.nih.gov). b populations (Table 1). Moreover, the association findings of the genes neuregulin 1 and D-amino-acid oxidase activator were originally identified in an isolated population through a classical positional cloning strategy. CANDIDATE LOCI AND GENES FOR BIPOLAR DISORDER AND SCHIZOPHRENIA IN ISOLATED POPULATIONS The chromosomal loci discussed in this review were primary selected based on four meta-analyses of STR-based genome scans. The first reported meta-analysis was a probability analysis, which combined reported P-values across 11 BP genome scans and 18 SZ scans in regions with clusters of positive scores. Significant evidence was found for loci on 13q and 22q for both BP disorder and SZ and on 8p for SZ only [Badner and Gershon, 2002]. Second, two rank-based genome scan meta-analyses were simultaneously published for SZ [Lewis et al., 2003] and BP disorder [Segurado et al., 2003]. The meta-analysis for SZ was based on 20 genome scans and resulted in genomewide significant evidence for linkage on chromosome 2p11–q22, but also clusters of nominally significant P values on chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p [Lewis et al., 2003]. Although none of the linked regions reached the criteria for genomewide significance in the rank-based meta-analysis of 18 BP disorder genome scans, the most significant loci (Po0.01) were observed on chromosomes 9p, 10q, 14q, and regions on chromosome 18 [Segurado et al., 2003]. Third, a combined analysis using the original genotype data from 11 BP genome scans was conducted, resulting in genomewide significant linkage to BP on chromosomes 6q and 8q [McQueen et al., 2005]. Altogether, several of these loci have also been identified in isolated populations for BP disorder and/or SZ and replicated in several other populations, including chromosomes 1p13.3–q23.3, 5q23.2–q34, 6q16–q27, 8p22–p21.1, 10q11.21– q22.1, 13q14–q34, and chromosome 18, with or without the identification of a putative susceptibility gene (Table 1). Though not significant in any meta-analysis, genomewide significant linkage was originally identified in an isolated population on chromosomes 12q21–q24 and repeatedly replicated Human Mutation DOI 10.1002/humu by independent research groups with the identification of a putative susceptibility gene. Last but not least, although chromosome 1q32–q42.1 was not originally identified in an isolated population nor supported by any meta-analysis, linkage and association was repeatedly identified in the Finnish isolated population (Table 1). We highlight and discuss in detail the linkage and association findings on these loci in chromosomal order. 1q32^q42.1 A balanced translocation t(1;11)(q42.1;q14.3), segregating with major mental illness in a large pedigree from Scotland, started the interest in chromosome 1q in psychiatric disorders [St Clair et al., 1990]. The chromosome 1 breakpoint is located at 1q42.1 and the significant linkage signal increased further after including BP and UP patients in the analysis together with SZ patients [Blackwood et al., 2001]. This locus gained great support from linkage and association studies performed in Finnish families [Hovatta et al., 1999]. The roots of the Finnish population reach over 2,000 years with an early settlement in south eastern Finland. In the 16th century, internal migrations by groups of farmers from the Southeast toward the North gave rise to regional subisolates (late settlement). Since then, a national system of population records was established, enabling the reconstruction of genealogical trees of very large multigenerational pedigrees today. In history, Finland has remained relatively genetically homogeneous compared to their neighboring countries due to geographical barriers, such as the many lakes, and sociocultural reasons, such as the Finnish language (Table 2) [Peltonen et al., 2000]. Hovatta et al. [1999] originally identified through linkage analysis a susceptibility locus on chromosome 1q32–q42 for SZ in an internal isolate of Finland founded by approximately 40 families at the end of the 17th century. In the next years linkage analyses performed in additional families, from subisolates as well as from the early settlement of Finland, further supported evidence for this SZ locus [Ekelund et al., 2000, 2001, 2004; Paunio et al., 2001]. Additional evidence for this susceptibility locus came from linkage studies in outbred populations [Detera-Wadleigh et al., 1999; Gurling et al., 2001; Hamshere et al., 2005]. HUMAN MUTATION 28(12), 1156^1170, 2007 TABLE 2. Population Antioquia (Colombia) Ashkenazi Jews CVCR (Costa Rica) Faroe Islands Finland^early Finland^late Iceland Israeli Arabs Northern Sweden Palau, Micronesia Portuguese islands SLSJ (Quebec) 1159 Overview Characteristics of the Isolated Populations Used for Genetic Analyses in BP Disorder and SZ Parent population Spanish1Amerindian Rhineland Jews Spanish1Amerindian Scandinavian Middle Europe Finland^early Scandinavian1Gaelic Middle East Finnish1Saamis Asian Portugal European ] of founders Not known Not known 286 families Several 100 Several 100 40^60 couples 8,000^20,000 Not known Several 100 Several 100 Not known Several 100 Further research in the Scottish pedigree led to the identification of two genes that were disrupted at the translocation breakpoint on chromosome 1q42.1, known as ‘‘disrupted in schizophrenia’’ (DISC1 [MIM] 605210] and DISC2 [MIM] 606271]) [Millar et al., 2000]. DISC2, which overlaps with DISC1 but transcribed in the opposite direction, is a small RNAonly gene that probably acts as a negative regulator of DISC1. The t(1;11) translocation directly disrupts DISC1 within intron 8, removing exons 9 to 13 to chromosome 11. Although an abnormal truncated protein product could not be found, a 50% reduction of DISC1 expression levels was observed, suggesting haploinsufficiency as the most probable disease mechanism [Millar et al., 2005]. An exon 12 frameshift mutation has also been identified, which introduces a stop codon, resulting in reduced expression levels of DISC1 without the presence of a truncated protein product [Sachs et al., 2005]. DISC1 interacts with a number of proteins in neurobiological pathways [reviewed by Porteous et al., 2006]. Additional support for the involvement of DISC1 came from association studies performed in the Finnish population [Ekelund et al., 2004; Hennah et al., 2003], as well as in outbred populations [reviewed by Porteous et al., 2006]. Of note is that unaffected t(1;11) carriers in the original pedigree showed an altered event related potential (ERP) P300 comparable with SZ and BP patients, which is a measure for cognitive abilities [Blackwood et al., 2001]. Since then, several studies in the Finnish population have shown evidence for linkage between the DISC1 locus and impaired working memory function [Gasperoni et al., 2003], visual working memory [Hennah et al., 2005], verbal learning memory [Paunio et al., 2004], and shortand long-term memory [Cannon et al., 2005]. 1p13.3^q23.3 More centromeric to 1q32–q42, clusters of nominally significant P values were found on chromosome 1p13.3–q23.3 in the SZ meta-analysis of Lewis et al. [2003]. Originally, a genomewide significant linkage signal was identified for SZ on chromosome 1q22 in 22 multigenerational Canadian families with Celtic and German ancestry, living in the isolated region of eastern Quebec [Brzustowicz et al., 2000]. Linkage studies in inbred [Fallin et al., 2004] and outbred [Gurling et al., 2001; Shaw et al., 1998] populations independently provided additional support for linkage of BP disorder and SZ with chromosome 1q21–q23. However, this region was not replicated by a large collaborative SZ study [Levinson et al., 2002]. Further follow-up of the candidate region by linkage disequilibrium (LD) mapping in the Canadian population led to the ] of generations 20 50 15^20 50^60 80^100 10^20 50^60 o30 o100 o100 20^40 10^20 Current population size Age of population (years) 45,000,000 11,200,000 3,000,000 45,000 45,000,000 o50,000 270,000 90,000 257,000 23,000 550.000 285,000 200^400 1,150 200^400 1,000 2,000 330 41,000 200 1,500 2,000 600 170 identification of NOS1AP as a gene for SZ susceptibility (earlier referred to as CAPON; MIM] 605551) [Brzustowicz et al., 2004], which was replicated in a Han Chinese population [Zheng et al., 2005]. However, no evidence for association was found in a UK sample [Puri et al., 2007]. NOS1AP encodes the nitric oxide synthase 1 (neuronal) adaptor protein and negatively regulates Nmethyl D-aspartate (NMDA)-type receptor-mediated glutamate neurotransmission by binding nitric oxide synthase. Expression analysis revealed overexpression of NOS1AP in brain of both SZ and BP patients, suggesting impaired NMDA receptor-mediated glutamate receptor neurotransmission [Xu et al., 2005]. This is in line with the hypothesis of a hypofunction of NMDA-mediated neurotransmission in the pathophysiology of these psychiatric disorders. 5q23.2^q34 Lewis et al. [2003] reported suggestive evidence for linkage on chromosome 5q23.2–q34 in their SZ meta-analysis, which is also a promising candidate region for SZ and BP disorder, mainly supported by linkage studies performed in Central American populations with a high degree of Spanish origin. Evidence for chromosome 5q as a SZ susceptibility locus has emerged from a linkage study of SZ families from the Central Valley of Costa Rica (CVCR) [DeLisi et al., 2002]. This very young population was founded by a limited number of Spanish and Amerindian families in the 16th century. Since the CVCR area is separated from the coastal regions by mountains, this population was kept geographically isolated until at least the late 19th century. Therefore, the 3 million people today almost entirely descend from 4,000 individuals from CVCR alive in 1700. The limited number of generations since founding (o20 generations) result in wider LD regions compared to other populations, enabling genomewide LD mapping using low-density STR-maps (Table 2) [Service et al., 2001]. Further support for a SZ-locus on chromosome 5q23.2–q35 has come from another population, of Mexican and Central American ancestry, with a high degree of Spanish and Amerindian origin [Escamilla et al., 2007], and other isolated populations, including the Portuguese islands [Sklar et al., 2004], Palau [Devlin et al., 2002], and Finland [Paunio et al., 2001], as well as from outbred populations [Gurling et al., 2001; Schwab et al., 1997; Straub et al., 1997]. The population of Palau, which is an archipelago of islands in Micronesia, is believed to have originated from at most a few hundred initial Asian founders 2,000 years ago. In history, the populations on these islands have developed in relative isolation, even from other Micronesian populations. A genetic bottleneck Human Mutation DOI 10.1002/humu 1160 HUMAN MUTATION 28(12), 1156^1170, 2007 due to a typhoon and exposure to Western diseases led to a dramatic decrease of the Micronesian population in the 19th century, after which the population increased to its current size of about 23,000 (Table 2) [Devlin et al., 2002]. Also for BP disorder, suggestive evidence for linkage and increased allele sharing identical by descent (IBD) among patients with BPI disorder was observed on chromosome 5q31–q33 in the isolated population of the CVCR [Garner et al., 2001; Hong et al., 2004]. The locus on chromosome 5q31–q33 was independently supported by genetic analysis in Colombian BP families, showing genomewide significant evidence for linkage on chromosome 5q31–q34 [Herzberg et al., 2006]. These families were ascertained in Antioquia, a historically isolated population from North West Colombia. This population is, like the CVCR population, a very young population (o20 generations), founded by a limited number of Spanish and Amerindian families in the 16th century and grown in relative isolation until recently (Table 2) [CarvajalCarmona et al., 2003]. Genetic studies showed a close relatedness between the Antioquian and CVCR population, with similar allele frequency distributions and LD patterns [Service et al., 2006]. 6q16^q27 The long arm of chromosome 6 has gained interest in BP disorder and SZ in the past few years. Moreover, chromosome 6q achieved genomewide significance in the most recent metaanalysis [McQueen et al., 2005], making it one of the best supported regions for BP disorder. Interestingly, the 6q locus has emerged from multiple genetic studies performed in several isolated populations. The 6q locus was first identified as a susceptibility locus for SZ in the geographically isolated county of Västerbotten in northern Sweden (Table 2). The earliest settlements in the county of Västerbotten occurred at least 8,000 years ago, but the current population dates back from a population admixture between Finns and Swedish Saamis approximately 1,500 years ago. This region has been historically and culturally an isolated area for a long time and remained isolated from other regions until the last century. Only after 1930, there has been a considerable decrease in isolation and inbreeding [Nylander and Beckman, 1991]. Like the Finnish population, the current northern Swedish population is a relatively old population (r100 generations) and Sweden also has a national system of population records dating back to the 16th century, which enables the reconstruction of genealogical trees for very large multigenerational pedigrees today (Table 2). A genome scan performed in a large 12-generation pedigree originating from northern Sweden pointed to a susceptibility locus on chromosome 6q25–q27 for SZ with genomewide significance [Lindholm et al., 2001] and a common ancestral haplotype inherited by the SZ patients in this pedigree [Lindholm et al., 2004]. Further fine mapping resulted in a 500-kb IBD haplotype, shared among the majority of the patients in the large family, and subsequent analysis in unrelated nuclear families from the same geographical area showed association of this haplotype with SZ. Quantitative PCR (QPCR)-based expression analysis of the only gene located in this region, the quaking homolog, KH domain RNA binding (mouse) (QKI; MIM] 609590), showed decreased expression levels of two QKI splice variants (QKI-7kb and QKI7kb-B) in the frontal cortex of SZ patients [Aberg et al., 2006b]. Furthermore, the splice variant QKI-7kb was shown to be responsible for decreased expression of oligodendrocyte-related and, in particular, myelin-related genes in the frontal cortex of SZ patients [Aberg et al., 2006a]. Together, these results suggest that Human Mutation DOI 10.1002/humu QKI expression levels regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as seen in the mouse. Myelin and oligodendrocyte dysfunction have been suggested as a pathomechanism for the development of SZ [reviewed in McInnes and Lauriat, 2006]. Recently, our group performed a genomewide scan in nine multigenerational families, segregating affective disorders and originating from the same geographic region in northern Sweden, and obtained significant evidence for linkage on chromosome 6q23–q24. Interestingly, 72% of the BP patients showed psychotic features in our study [Venken et al., 2005]. Together, these data support the presence of a shared susceptibility gene on chromosome 6q for affective disorders and SZ in the northern Swedish population. However, whether QKI is also associated with affective disorders in the northern Swedish population needs to be elucidated. Additional support for chromosome 6q as a susceptibility locus for SZ came from the relatively homogeneous Arab Israeli population. This population is an ethnically homogeneous group, originating from towns that were founded approximately 200 to 250 years ago by a limited number of families. A high birth rate, an unusually high level of consanguinity and a low rate of intermarriage with other ethnic populations in Israel characterize these communities (Table 2). Linkage analysis in 21 SZ families from this population resulted in genomewide significant linkage on 6q23 [Lerer et al., 2003]. Subsequent fine mapping in this region revealed a higher linkage signal in a more delineated region of 7 Mb linked with SZ [Levi et al., 2005]. Further investigation of this candidate region in an extended set of nuclear families of the inbred Arab Israeli population showed significant association with SNPs and haplotypes in a 500-kb region. Association analysis in a replication sample of 209 nuclear Arab outbred families segregating SZ resulted in significantly associated haplotypes comprised of the same SNPs that were associated in the inbred families. However, no shared haplotype was observed between the two populations. This region harbors two genes, including the brain-expressed Abelson helper integration site 1 (AHI1; MIM] 608894), which might be involved in brain development, and the adjacent primate-specific gene C6orf217 with unknown function. Since these two genes are transcribed in opposite orientations, their regulatory regions might overlap and both genes might influence the expression of each other [Amann-Zalcenstein et al., 2006]. Also, significant evidence for linkage at chromosome 6q with BP disorder has emerged from families originating from the Portuguese islands. These islands include Madeira and the Azores, a nine-island archipelago located in the Atlantic Ocean. They have a similar history, with a settlement by Portuguese founders in the early 1400s, church records, and a centralized health system (Table 2) [Pato et al., 1997]. A first genomewide scan in 16 multigenerational families identified a linkage signal on chromosome 6q16–q21, which increased further after fine mapping [Pato et al., 2004]. In a follow-up study [Middleton et al., 2004], a 10K genomewide SNP assay was used for linkage analysis in an extended sample of 25 families, of which 12 families were originally used in the study of Pato et al. [2004]. These 12 families enabled researchers to make a comparison between results of the traditional 10-cM density STR genomewide scan and the 10K SNP chip. Using the high density SNP assay, the linkage signal on chromosome 6 increased to genomewide significance on chromosome 6q22 and the complete set of 25 families even further strengthened these findings [Middleton et al., 2004]. HUMAN MUTATION 28(12), 1156^1170, 2007 Chromosome 6q has gained further evidence for linkage for BP disorder and SZ from outbred populations of Danish [Ewald et al., 2002a], Austrian [Bailer et al., 2002], U.S. [Dick et al., 2003], and UK/Irish origin [Lambert et al., 2005]. Together, these findings provide strong support for at least one susceptibility gene on chromosome 6q for affective disorders and/or SZ. 8p22^p21.1 Two genome scan–based meta-analyses identified chromosome 8p as a susceptibility locus for SZ [Badner and Gershon, 2002; Lewis et al., 2003]. Chromosome 8p22–p21.1 was originally identified in a SZ genome scan in U.S. families, resulting in suggestive evidence for linkage [Pulver et al., 1995], which increased to a significant level after fine mapping [Blouin et al., 1998]. This locus has gained support for linkage with SZ by independent studies [reviewed by Harrison and Law, 2006]. A significant contribution to these findings was provided by genetic analysis in the Icelandic population. Iceland was founded more than 1,100 years ago by a limited number of settlers of mainly Scandinavian males and Gaelic females. Little immigration has occurred in the past 11 centuries and the population expanded rapidly after 1850 to its current size of 290,000 inhabitants. It has been shown that the Icelandic population is characterized by low genetic diversity [Helgason et al., 2003], likely due to its history and geographical isolation. Moreover, the Icelandic health system is organized around a large genealogy database covering the entire present day population and stretching back to the founding of the country. Along with these genealogical records, national medical data are combined with genetic research in large extended pedigrees by the deCODE project (Table 2) [Peltonen et al., 2000]. Stefansson et al. [2002] performed a genomewide scan in 33 Icelandic SZ families resulting in a suggestive linkage peak on chromosome 8p21–p12. Subsequent LD mapping across this locus in an Icelandic SZ population resulted in the identification of neuregulin 1 (NRG1; MIM] 142445) as a SZ candidate gene, with a seven-marker ‘‘high-risk’’ haplotype located at the 50 end of NRG1 (HAPICE, represented by a ‘‘core’’ haplotype of three markers, including one SNP and two STRs). None of the individual SNPs showed significant association with SZ as high as HAPICE, suggesting that neither one of the identified variants was the functional polymorphism. However, hypomorphic mice (mutant mice heterozygous for either NRG1 or its receptor ErbB4) exhibited behavioral abnormalities, which overlap with mouse models for SZ, and these were partially reversible with clozapine, an atypical antipsychotic drug. Furthermore, binding studies showed that the number of NMDA receptors in the NRG1 hypomorphic mice was reduced, which was also observed in the brain of SZ patients [Ibrahim et al., 2000; Stefansson et al., 2002]. The human NRG1 gene is a large gene covering approximately 1.4 Mb of the genome and contains more than 20 exons which result in multiple functionally distinct isoforms, detected in neurons of many areas of developing and adult human brain. NRG1 is a growth factor by acting as a ligand for ErbB receptor tyrosine kinases. NRG1-mediated activation of these epidermal growth factor (EGF) receptors modulates postsynaptic transcriptional activity. The large number of NRG1 isoforms and signaling mechanisms correspond to the wide range of its functional effects. These include neuronal and glial functions, ranging from development (such as neuronal specification and migration, axon guidance, synaptogenesis, neuron-glial signaling, glial development and differentiation, and myelination) to neurotransmission and 1161 synaptic plasticity (such as regulation of NMDA, GABA, and nicotinic receptors, and modulation of long-term potentiation). These processes, influenced by NRG1, overlap with pathways and processes, which have been implicated before in SZ. The NRG1 neurobiology in SZ is further reviewed in detail by Harrison and Law [2006]. However, at this moment it remains impossible to predict which of the specific NRG1 functions could be most relevant to SZ. Overall, the majority of reported association studies, particularly in Caucasians, found association with the 50 region covering the first two exons of NRG1. In contrast, studies in the Chinese population found association in the 30 region. However, two recently published meta-analyses of association studies gave strong support for association between NRG1 and SZ [Li et al., 2006; Munafo et al., 2006]. Furthermore, several positive [Addington et al., 2007; Fukui et al., 2006; Kim et al., 2006; Walss-Bass et al., 2006] as well as two negative association studies [Duan et al., 2005; Ingason et al., 2006] have been reported since then. The core HAPICE risk haplotype was also associated with BP disorder, with stronger evidence in BP patients with psychotic features that were predominantly mood incongruent [Green et al., 2005]. Recently, a haplotype tagging SNP (htSNP)-based association study of NRG1 in a second cohort of the Scottish population showed association with both BP disorder and SZ in a 136-kb region in the 30 region of NRG1 [Thomson et al., 2007]. Altogether, these results argued convincingly that NRG1 is likely a susceptibility gene for SZ and BP disorder. 10q11.21^q22.1 Although none of the linked regions reached the criteria for genomewide significance in the BP meta-analysis of Segurado et al. [2003], chromosome 10q11.21–q22.1 was one of the most significant loci. Linkage of BP disorder and SZ to chromosome 10q is observed in several ethnic populations, ranging from 10q21 to 10q26 and has gained great support from the Ashkenazi Jewish population. The current Ashkenazi Jewish population, living mostly in Central and Eastern Europe and the United States, descended from a small founder population about 500 years ago. The rate of admixture is estimated to be low probably due to the cultural and social isolation of this population characterized by endogamy. Despite migration and spacing all over the world, the Ashkenazi Jewish population has maintained their religious as well as genetic identity (Table 2) [Ostrer, 2001]. Fallin et al. [2003] specifically studied linkage in 29 Ashkenazi Jewish SZ families and observed significant evidence for linkage in a 12.2-Mb region on chromosome 10q22. Additionally, in a linkage study on BP disorder of the same research group in 41 Ashkenazi Jewish families, support for linkage was found for the same region [Fallin et al., 2004]. Independently, our group provided evidence for genomewide significant linkage with a 14-marker haplotype on chromosome 10q21.3–q22.3, shared by the patients diagnosed with affective disorders of a large multigenerational Ashkenazi Jewish family [Venken et al., 2007]. Since reduced genetic variation is expected in this population, a common susceptibility gene on chromosome 10q22 for both BP disorder and SZ might be present in this isolated population. The 10q locus gained additional support through linkage in several outbred populations [Cheng et al., 2006; Cichon et al., 2001; Etain et al., 2006; Faraone et al., 2006; Kelsoe et al., 2001; Liu et al., 2004; McInnis et al., 2003; Wildenauer and Schwab, 1999; Williams et al., 2003] as well as in isolated populations, including in Arab Israeli SZ families [Lerer et al., 2003], in a large Human Mutation DOI 10.1002/humu 1162 HUMAN MUTATION 28(12),1156^1170, 2007 BP pedigree from a homogeneous population in the eastern part of Cuba [Marcheco-Teruel et al., 2006] and increased haplotype sharing in patients with BP disorder and SZ from the isolated Faroe Islands [Ewald et al., 2002b]. The Faroe Islands are a small group of islands situated between Norway, Scotland, and Iceland. These islands have been settled more than 1,000 years ago by a small number of Scandinavian founders. In history, this population has known a limited expansion through many generations, periods with reduction in population size due to severe epidemics and famine, little immigration, and recent expansion to its current size of about 45,000. Also, the Faroe Islands have church records dating back to the 17th century (Table 2) [Ewald et al., 2002b]. Recently, an association was reported for GRID1 (glutamate receptor, ionotropic, delta 1; MIM] 610659) with SZ as well as with BPI disorder and SZ/SA disorder combined in the Ashkenazi Jewish population. GRID1 might be involved in glutamatergic signaling, since it is highly related to ionotropic glutamate receptor subunits [Fallin et al., 2005]. 12q21^q24 Originally, a genomewide scan in a 10-generational BP pedigree, originating from the founding population of the Saguenay-Lac-StJean (SLSJ) area in Eastern Quebec, resulted in genomewide significant linkage on chromosome 12q23–q24 and was subsequently confirmed in a second large BP pedigree from the same population [Morissette et al., 1999]. The settlement of this founding population of European origin occurred around 1830 and since this date genealogical records are available. Due to cultural differences and religious beliefs with surrounding communities, the SLSJ community remained isolated (Table 2). Reanalyzing the undivided pedigree of the genome scan did not support the presence of a shared haplotype by patients [Shink et al., 2003], since two predominant haplotypes were originally seen in the patients when the pedigree was subdivided in five branches [Morissette et al., 1999]. Therefore, the researchers concluded that, although less genetic heterogeneity would be expected by the history of the population, genetic heterogeneity still exists in this population [Shink et al., 2003]. However, a smaller IBD region might be present in the patients, which might have been detected using a denser marker map. Linkage analysis of 18 extra families from the SLSJ area also showed genome-wide significant evidence of a BP susceptibility locus on chromosome 12q23–q24 [Shink et al., 2005b]. Additional fine mapping in 41 BP families and association analysis in the SLSJ population pointed to a marker, located within intron 9 of P2RX7 (purinergic receptor P2X, ligandgated ion channel, 7; MIM] 602566) [Shink et al., 2005a]. Further investigation of a 200-kb region around this marker revealed significant association with SNPs and haplotypes in P2RX7 and an overtransmission of the mutant allele of a nonsynonymous polymorphism (p.Q460R) located in the intracellular C-terminal domain [Barden et al., 2006]. P2RX7 encodes an ATP-gated P2X receptor, which is a cation-selective ion channel with high calcium permeability when stimulated by binding of ATP. Recent studies showed a neuroprotective effect of ATP-induced P2RX7 by stimulating microglia and astrocytes in neuronal survival and neurogenesis [Walter et al., 2004]. Since the C-terminal domain is essential for normal function of the receptor, p.Q460R might influence its function. Therefore, replication in other association studies and further research of the functional impact of p.Q460R on P2RX7 are necessary. Additional support, although suggestive, for linkage with SZ and BP disorder in this region was found in other families from the Human Mutation DOI 10.1002/humu Province of Quebec [Brzustowicz et al., 2000; Maziade et al., 2005]. Independently, other research groups identified genomewide significant evidence for chromosome 12q23–q24 in outbred populations for BP and UP disorder [Abkevich et al., 2003; Curtis et al., 2003; Ewald et al., 2002a]. Of note is that linkage for BP disorder was supported in Finnish families [Ekholm et al., 2003] as well as increased haplotype sharing and allelic association on 12q24 was observed in BP patients from the isolated Faroe Islands [Degn et al., 2001]. Also, chromosome 12q23–q24.1 is implicated by two pedigrees, cosegregating both affective disorders and Darier’s disease, which is a rare autosomal dominant skin disease caused by mutations in the ATP2A2 gene (MIM] 108740) encoding a Ca21 pump [Craddock et al., 1994; Jones et al., 2002]. Together, these findings strongly suggest the existence of a susceptibility gene for major affective disorders and SZ on chromosome 12q22–q24, with most evidence for BP disorder. Although overlap exists between the candidate regions identified in the different studies, the linkage signals extend over a large distance on chromosome 12q. Therefore, other susceptibility genes on chromosome 12q might (additionally) be involved in the predisposition of these psychiatric disorders, of which DAO and TPH2 have gained support from isolated populations. D-amino-acid oxidase (DAO; MIM] 124050) located on chromosome 12q24 is involved in the glutamate pathway by regulating the concentration of D-serine, a potent activator of NMDA receptors. Chumakov et al. [2002] found significant association between four SNPs in DAO and SZ in a French Canadian population, also originating from the Province of Quebec and experimentally shown to be genetically homogeneous, along with some indication that SNPs in DAO and G72 (MIM] 607408) might act in combination to influence the risk for SZ. To date, DAO is only investigated in a few association studies and mainly in SZ patients, including one negative (Liu et al., 2006) and two positive findings [Liu et al., 2004; Wood et al., 2007]. Additionally, a German study showed association between DAO SNPs and SZ but not BP disorder [Schumacher et al., 2004]. Association between DAO and BP disorder was found in a genetically homogeneous Ashkenazi Jewish population, further supporting a role in the vulnerability of these psychiatric disorders [Fallin et al., 2005]. The brain-specific tryptophan hydroxylase 2 (TPH2; MIM] 607478), cytogenetically located on chromosome 12q21.1, is the rate-limiting enzyme in the serotonin biosynthetic pathway and is involved in the regulation of serotonin levels. Zill et al. [2004a] reported association with SNPs and haplotypes between TPH2 and UP disorder. Since the positive linkage signal extended to chromosome 12q21 in the large pedigree of the SLSJ area [Morissette et al., 1999], this gene was further investigated in an association study resulting in haplotype association between TPH2 and BP disorder in the SLSJ population [Harvey et al., 2004]. Our group provided additional evidence by a htSNP based study performed in a genetically homogeneous patient–control sample from northern Sweden, covering maximal genetic variability of TPH2. SNP based association was found in the upstream regulatory region of TPH2 for both UP and BP disorder. Haplotype analysis supported this significant result by the presence of a protective haplotype [Van Den Bogaert et al., 2006]. Five additional genetic association studies reported significant associations between TPH2 and UP disorder, suicide, and BP disorder, further supporting the involvement of TPH2 in the pathogenesis of affective disorders [Ke et al., 2006; Lopez et al., 2007; Zhang et al., 2005; Zhou et al., 2005b; Zill et al., 2004b]. Recently, Zhang et al. [2005] found a functional c.1322A4G HUMAN MUTATION 28(12), 1156^1170, 2007 (p.R441H) human missense mutation linked to major depression. However, several research groups did not find this mutation in a total number of 4,227 UP patients, 480 BP patients, 425 patients with other psychiatric disorders, and 1,789 control individuals, suggesting that this variant is at best very rare [Delorme et al., 2006; Garriock et al., 2005; Glatt et al., 2005; Van Den Bogaert et al., 2005; Zhou et al., 2005a]. 13q12^q34 Up to date, six SZ and 12 BP linkage studies with NPL or LOD scores 42 on chromosome 13q have been reported by several independent research groups and provided accumulating evidence of significant linkage of these psychiatric disorders with a large region on chromosome 13q, spanning more than 60 Mb ranging from 13q12 to 13q34 [reviewed by Detera-Wadleigh and McMahon, 2006]. One of these studies was performed in 21 Canadian families, originating from a genetically homogeneous population of Eastern Quebec, with Celtic and German ancestry, resulting in a significant LOD score to a broad spectrum of SZ at chromosome 13q32 [Brzustowicz et al., 1999]. Additional support to this linkage peak was provided for SZ as well as for BP disorder by a meta-analysis [Badner and Gershon, 2002]. Chumakov et al. [2002] further investigated the distal 5-Mb part of the 13q chromosomal candidate region, applying a dense LD map of SNPs in a French Canadian population also originating from the Province of Quebec and experimentally shown to be genetically homogeneous. Association analysis revealed two smaller regions with associated SNPs to SZ. Especially in one of these regions the significant SNPs were clustered in a 65-kb region in which haplotype analysis provided additional support for significant association. Furthermore, the association with SZ in this region was replicated in an association sample of Russian origin by genotyping a subset of SNPs. The markers in this 65-kb region were located in and around two novel genes, G72 (MIM] 607408) and G30 (MIM] 607415), which overlap and are transcribed in opposite orientation. Moreover, G72 but not G30 gave a translation product, suggesting that only G72 is actively translated. Further analysis revealed a functional interaction of G72 with DAO, enhancing the activity of DAO [Chumakov et al., 2002]. Subsequently, G72 has been named D-amino-acid oxidase activator (DAOA). DAO oxidizes and regulates the concentration of D-serine, a potent activator of the NMDA-type glutamate receptor. NMDA receptors are ligand-gated ion channels, which have a recognition site for glycine and D-serine. In the presence of glutamate, binding of these ligands will stimulate ion flow. Since expression studies showed increased transcription levels of DAOA in the dorsolateral prefrontal cortex of postmortem brains from SZ patients [Korostishevsky et al., 2004], DAOA might play a role in the regulation of NMDA receptors by inhibiting its function through stimulation of DAO-activity. This is in line with the hypothesis of a hypofunction of NMDA-mediated neurotransmission in the pathophysiology of psychiatric disorders. Since G72 seems to be primate specific [Chumakov et al., 2002], no animal studies have been performed yet to further investigate the biological role of its protein product. Association studies between DAOA and SZ as well as BP disorder and panic disorder have subsequently been reported. A meta-analysis was performed on a total number of 10 association studies, showing highly significant evidence of association between the DAOA-region and SZ and significant evidence of association with BP disorder [Detera-Wadleigh and McMahon, 2006]. Since this meta-analysis, one negative finding for SZ in a Taiwanese 1163 population [Liu et al., 2006] and several positive associations have been published for BP disorder and SZ by independent research groups in two isolated populations, the Ashkenazi Jewish [Fallin et al., 2005] and Palestinian Arab population [Korostishevsky et al., 2006] as well as in outbred populations [Hong et al., 2006; Ma et al., 2006; Schulze et al., 2005; Williams et al., 2006]. At this moment the finding for DAOA may be the strongest reported evidence for association with BP disorder. However, there is no consistency across studies concerning associated alleles or haplotypes and, although one nonsynonymous variant (rs2391191, p.K29R) was significantly associated with SZ, further unidentified predisposing variants in this region need to be identified to explain the complex pattern of association. Chromosome 18 In the meta-analysis of Segurado et al. [2003], several regions along chromosome 18 have been identified as loci potentially harboring susceptibility genes for BP disorder, including 18pter-p11 and 18p11–q12.3. A genome scan performed in two large families segregating BPI disorder from CVCR initially showed suggestive evidence for linkage on chromosome 18q22–q23 and 18p11.3 [Freimer et al., 1996; McInnes et al., 1996]. These candidate regions and chromosome 18 as a whole were followed up in the CVCR by further fine mapping, extending the BP study sample or using alternative methods, including LD-mapping and different software algorithms. Together these results gave additional support for the presence of a risk factor for BP disorder on chromosome 18pter–p11 [Escamilla et al., 2001; McInnes et al., 2001] and 18q22–q23 [Escamilla et al., 1999; Garner et al., 2001]. Furthermore, chromosome 18q12.2–q12.3 may also encompass a susceptibility gene for BP disorder [Escamilla et al., 2001]. Recently, suggestive evidence for linkage was found with SZ and psychosis on 18p11 in families of Mexican and Central American origin, suggesting the presence of a common risk factor for these severe psychiatric disorders in general on chromosome 18p11 inherited by the Spanish founders, who emigrated from the Spanish empire to Central America in the 15th and 16th century [Escamilla et al., 2007]. CONCLUSIONS In the last decade, a number of independent replicated linkage findings for major affective disorders and SZ have emerged. Moreover, there is a growing body of evidence for the involvement of a number of genes in the etiology of these psychiatric disorders. However, the extensive genetic research has also resulted in many inconsistent findings, including different associated susceptibility alleles and/or haplotypes or even failure of replication. Isolated populations have contributed to these positive as well as negative findings. Importantly, promising findings in psychiatric genetics, such as NRG1 and DAOA, were originally identified in an isolated population. Though multiple independent research groups replicated these findings, several negative findings have been reported as well. Furthermore, some putative susceptibility loci and/or genes that were identified in isolated populations still need replication. Are isolated populations then not as useful as one may think? And are the genes or susceptibility alleles in these populations not epidemiologically relevant? Failure of replication might result from a spurious positive finding in the original report, caused by type I error. On the other hand, lack of statistical power of some individual studies, due to a small sample size or high genetic heterogeneity in the studied population, can also result in failure of replication. Furthermore a Human Mutation DOI 10.1002/humu 1164 HUMAN MUTATION 28(12), 1156^1170, 2007 gene, which might play only a minor role in disease risk in the general population, might be an important risk factor in an isolated population. Therefore, it may occur as a common allele in the isolated population but as a rare allele in the general population, which will be difficult to detect in classical association studies. Also, the identification of a gene or allele that clinically and/or genetically is not as important in outbred populations as in isolated populations might unravel biological pathways and uncover new candidate genes, which might have a higher impact on disease risk in general. The failure to replicate some single-gene results might also result from an underlying genetic architecture in which gene–gene and/or gene–environment interactions are involved. Isolated populations are characterized by increased homogeneity, since they are likely to have both a reduced number of genetic vulnerability factors and environmental background, increasing the chance of finding the underlying genes. Therefore, it will be important to take these interactions into account in genetic studies, especially in heterogeneous outbred populations. Nevertheless, there will be more than one susceptibility gene that increases disease risk in isolated populations as well, as is evidenced in some studies where not all the patients of an extended pedigree shared the same haplotype, augmenting conditioned analysis in these populations as well. In association studies, the individuals under study are intended to be unrelated. However, now-living individuals of isolated populations descended from a few common founders in history and there is a higher probability that two random individuals are related compared to outbred populations. Failing to take into account extended familial relationships in association studies can produce false-positive results, missing true associations while overestimating the level of significance. Therefore, it is important to use proper statistical methods for isolated populations accounting for this genealogical relatedness between ‘‘unrelated’’ patients and control individuals [reviewed in Bourgain and Genin, 2005]. Though isolated populations are considered to be more homogeneous than outbred populations, population structure can still be present in these populations. Since individuals of an isolate tend to mate with their neighbors and settle close to their birthplaces over a number of generations, there is a closer genealogical relationship to their neighbors with more IBD regions and similar allele frequencies in certain subregions. However, there might be small but measurable differences between subregions, leading to false positive results for some diseases. This is evidenced in Iceland, where based on genetic data considerable variance was identified among ancestors within individuals but also among counties, resulting in geographical stratification [Helgason et al., 2005]. Therefore, sampling strategies need to take substructure into account and genetic testing by genomic controls should be applied, even in isolated populations. The negative findings in replication studies also point to the importance of a comprehensive study of a candidate locus/gene, using an LD mapping strategy. Differences in ethnicity might underlie some of the discrepant findings in association studies, considering single marker and haplotype findings. In fact, the risk factor might be present on a different ancestral haplotype or a new mutation might have arisen in time in another ethnic population. Therefore, researchers should not only use the associated variants in their replication efforts, as has been the case in many follow-up studies. Instead they should perform a systematic screening covering complete genetic variability of the whole gene under study. Until recently, this was a major effort, by first screening the Human Mutation DOI 10.1002/humu gene or region of interest for variants, followed by the characterization of the LD pattern across the region, then defining the set of variants that capture maximally the genetic variability (tagging SNPs or tSNPs) to finally dissect the relevance of associated variants to the disorder. This has now become feasible with the International Haplotype Map (HapMap) project, which provides publicly available genetic SNP data in four different populations (www.hapmap.org) [International HapMap Consortium, 2003, 2005]. These data enable the characterization of the LD pattern across the region of interest, without first systematically screening this region for variants. Furthermore, the same set of tSNPs can then be used in independent replication studies as well, facilitating comparison between studies and meta-analyses. However, one can hypothesize that HapMap data might not be applicable to other populations, such as isolated populations. This can only be evidenced if all the HapMap SNPs are typed in the populations of interest. Recently, studies have shown similar LD patterns and block structure in an Australian and several European populations as in the HapMap CEU population, suggesting that the HapMap data is reliable for tSNP selection in other populations [Ribas et al., 2006; Smith et al., 2006; Stankovich et al., 2006; Willer et al., 2006]. Furthermore, new techniques, such as high-density SNP chips, will enable the identification of IBD regions much faster, not only in young isolated populations with wider LD regions across the genome such as the Central American populations, but also in older populations. Nevertheless, isolated populations have been of great value in the identification of a number of susceptibility loci/genes for BP disorder and SZ, of which some are strongly supported today by several meta-analyses. Interestingly, chromosome 6q, one of the most replicated linkage regions for BP disorder to date has emerged from multiple genetic studies performed in several isolated populations, all showing genome-wide significant evidence for linkage. Furthermore, chromosome 1q32–q42.1 encompassing DISC1, originally identified through a balanced translocation, is repeatedly identified in the Finnish population with significant association of the gene itself. DISC1 has now emerged as a key molecular player in SZ and in normal brain processes. Importantly, NRG1 and DAOA are the major examples of the success of genetic studies performed in isolated populations, since these genes were originally identified in the isolated Icelandic and French Canadian population respectively. During the last few years, NRG1 and DAOA are both considered as one of the most compelling findings in psychiatric genetics [reviewed in DeteraWadleigh and McMahon, 2006; Harrison and Law, 2006]. Especially for SZ, there is strong evidence for the involvement of NRG1 [Harrison and Law, 2006] and to a lesser extent for DAOA. At this moment the finding for DAOA may be the strongest reported evidence for association with BP disorder [DeteraWadleigh and McMahon, 2006]. Altogether, the above-mentioned loci and genes are today considered as major findings in psychiatric genetics in general. Moreover, three of the four strongest supported genes for BP disorder and SZ were originally identified or greatly supported in isolated populations. These findings point to the importance of a study sample with increased genetic homogeneity, in order to distinguish this locus from a reduced genetic background. Therefore, one can say that isolated populations provided a major contribution to the most significant findings in psychiatric genetics. At the moment, no variant with high functional impact has been identified for one of the identified genes for affective disorders or SZ. However, new faster and cheaper techniques HUMAN MUTATION 28(12), 1156^1170, 2007 (such as high-density SNP chips), combined with other strategies (such as HapMap or the use of clinical subgroups) as well as approaches that are proven to be successful (such as isolated populations), further extensive genetic investigation of susceptibility genes, functional studies of putative risk alleles and interaction analysis will increase the chance to unravel the molecular genetics and pathogenesis of these psychiatric disorders. REFERENCES Aberg K, Saetre P, Jareborg N, Jazin E. 2006a. Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc Natl Acad Sci USA 103:7482–7487. Aberg K, Saetre P, Lindholm E, Ekholm B, Pettersson U, Adolfsson R, Jazin E. 2006b. Human QKI, a new candidate gene for schizophrenia involved in myelination. Am J Med Genet B Neuropsychiatr Genet 141:84–90. Abkevich V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC, Plenk AM, Lowry MR, Richards RL, Carter C, Frech GC, Stone S, Rowe K, Chau CA, Cortado K, Hunt A, Luce K, O’Neil G, Poarch J, Potter J, Poulsen GH, Saxton H, Bernat-Sestak M, Thompson V, Gutin A, Skolnick MH, Shattuck D, Cannon-Albright L. 2003. Predisposition locus for major depression at chromosome 12q22–12q23.2. Am J Hum Genet 73:1271–1281. Addington AM, Gornick MC, Shaw P, Seal J, Gogtay N, Greenstein D, Clasen L, Coffey M, Gochman P, Long R, Rapoport JL. 2007. Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories. Mol Psychiatry 12: 195–205. Amann-Zalcenstein D, Avidan N, Kanyas K, Ebstein RP, Kohn Y, Hamdan A, Ben Asher E, Karni O, Mujaheed M, Segman RH, Maier W, Macciardi F, Beckmann JS, Lancet D, Lerer B. 2006. AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia. Eur J Hum Genet 14:1111–1119. Badner JA, Gershon ES. 2002. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 7:405–411. Bailer U, Leisch F, Meszaros K, Lenzinger E, Willinger U, Strobl R, Heiden A, Gebhardt C, Doge E, Fuchs K, Sieghart W, Kasper S, Hornik K, Aschauer HN. 2002. Genome scan for susceptibility loci for schizophrenia and bipolar disorder. Biol Psychiatry 52:40–52. Barden N, Harvey M, Gagne B, Shink E, Tremblay M, Raymond C, Labbe M, Villeneuve A, Rochette D, Bordeleau L, Stadler H, Holsboer F, Muller-Myhsok B. 2006. Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 141:374–382. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. 2001. Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 69: 428–433. Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G, Thornquist M, Ullrich G, McGrath J, Kasch L, Lamacz M, Thomas MG, Gehrig C, Radhakrishna U, Snyder SE, Balk KG, Neufeld K, Swartz KL, DeMarchi N, Papadimitriou GN, Dikeos DG, Stefanis CN, Chakravarti A, Childs B, Pulver AE. 1998. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 20:70–73. Bourgain C, Genin E. 2005. Complex trait mapping in isolated populations: are specific statistical methods required? Eur J Hum Genet 13:698–706. Brzustowicz LM, Honer WG, Chow EW, Little D, Hogan J, Hodgkinson K, Bassett AS. 1999. Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genet 65:1096–1103. Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett AS. 2000. Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science 288:678–682. Brzustowicz LM, Simone J, Mohseni P, Hayter JE, Hodgkinson KA, Chow EW, Bassett AS. 2004. Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22. Am J Hum Genet 74:1057–1063. 1165 Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. 2005. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 62:1205–1213. Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. 2002. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry 159:539–545. Carvajal-Carmona LG, Ophoff R, Service S, Hartiala J, Molina J, Leon P, Ospina J, Bedoya G, Freimer N, Ruiz-Linares A. 2003. Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica. Hum Genet 112:534–541. Cheng R, Juo SH, Loth JE, Nee J, Iossifov I, Blumenthal R, Sharpe L, Kanyas K, Lerer B, Lilliston B, Smith M, Trautman K, Gilliam TC, Endicott J, Baron M. 2006. Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorder. Mol Psychiatry 11:252–260. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon AM, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan JJ, Bouillot M, Sambucy JL, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham PC, Straub RE, Weinberger DR, Cohen N, Cohen D, Ouelette G, Realson J. 2002. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 99:13675–13680. Cichon S, Schmidt-Wolf G, Schumacher J, Muller DJ, Hurter M, Schulze TG, Albus M, Borrmann-Hassenbach M, Franzek E, Lanczik M, Fritze J, Kreiner R, Weigelt B, Minges J, Lichtermann D, Lerer B, Kanyas K, Strauch K, Windemuth C, Baur MP, Wienker TF, Maier W, Rietschel M, Propping P, Nothen MM. 2001. A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25–q26. Mol Psychiatry 6: 342–349. Craddock N, McGuffin P, Owen M. 1994. Darier’s disease cosegregating with affective disorder. Br J Psychiatry 165:272. Craddock N, O’Donovan MC, Owen MJ. 2005. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 42: 193–204. Craddock N, Forty L. 2006. Genetics of affective (mood) disorders. Eur J Hum Genet 14:660–668. Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O’Neill J, Smyth C, Moloney E, Murphy P, McQuillin A, Petursson H, Gurling H. 2003. Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23–q24, and suggests the presence of additional loci on 1p and 1q. Psychiatr Genet 13:77–84. Dean M. 2003. Approaches to identify genes for complex human diseases: lessons from Mendelian disorders. Hum Mutat 22:261–274. Degn B, Lundorf MD, Wang A, Vang M, Mors O, Kruse TA, Ewald H. 2001. Further evidence for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing and allelic association in patients from the Faroe Islands. Mol Psychiatry 6: 450–455. DeLisi LE, Mesen A, Rodriguez C, Bertheau A, LaPrade B, Llach M, Riondet S, Razi K, Relja M, Byerley W, Sherrington R. 2002. Genomewide scan for linkage to schizophrenia in a Spanish-origin cohort from Costa Rica. Am J Med Genet 114:497–508. Delorme R, Durand CM, Betancur C, Wagner M, Ruhrmann S, Grabe HJ, Nygren G, Gillberg C, Leboyer M, Bourgeron T, Courtet P, Jollant F, Buresi C, Aubry JM, Baud P, Bondolfi G, Bertschy G, Perroud N, Malafosse A. 2006. No human tryptophan hydroxylase-2 gene R441H Human Mutation DOI 10.1002/humu 1166 HUMAN MUTATION 28(12), 1156^1170, 2007 mutation in a large cohort of psychiatric patients and control subjects. Biol Psychiatry 60:202–203. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G, Rollins DY, Moses T, Sanders AR, Karkera JD, Esterling LE, Zeng J, Ferraro TN, Guroff JJ, Kazuba D, Maxwell ME, Nurnberger JI Jr, Gershon ES. 1999. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 96:5604–5609. Detera-Wadleigh SD, McMahon FJ. 2006. G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry 60:106–114. Devlin B, Bacanu SA, Roeder K, Reimherr F, Wender P, Galke B, Novasad D, Chu A, TCuenco K, Tiobek S, Otto C, Byerley W. 2002. Genomewide multipoint linkage analyses of multiplex schizophrenia pedigrees from the oceanic nation of Palau. Mol Psychiatry 7:689–694. Dick DM, Foroud T, Flury L, Bowman ES, Miller MJ, Rau NL, Moe PR, Samavedy N, El Mallakh R, Manji H, Glitz DA, Meyer ET, Smiley C, Hahn R, Widmark C, McKinney R, Sutton L, Ballas C, Grice D, Berrettini W, Byerley W, Coryell W, DePaulo R, MacKinnon DF, Gershon ES, Kelsoe JR, McMahon FJ, McInnis M, Murphy DL, Reich T, Scheftner W, Nurnberger JI Jr. 2003. Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet 73: 107–114. Duan J, Martinez M, Sanders AR, Hou C, Krasner AJ, Schwartz DB, Gejman PV. 2005. Neuregulin 1 (NRG1 ) and schizophrenia: analysis of a US family sample and the evidence in the balance. Psychol Med 35: 1599–1610. Ekelund J, Lichtermann D, Hovatta I, Ellonen P, Suvisaari J, Terwilliger JD, Juvonen H, Varilo T, Arajarvi R, Kokko-Sahin ML, Lonnqvist J, Peltonen L. 2000. Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 9:1049–1057. Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R, Suhonen J, Ellonen P, Chan G, Sinsheimer JS, Sobel E, Juvonen H, Arajarvi R, Partonen T, Suvisaari J, Lonnqvist J, Meyer J, Peltonen L. 2001. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 10:1611–1617. Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lonnqvist J, Peltonen L. 2004. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry 9:1037–1041. Ekholm JM, Kieseppa T, Hiekkalinna T, Partonen T, Paunio T, Perola M, Ekelund J, Lonnqvist J, Pekkarinen-Ijas P, Peltonen L. 2003. Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder. Hum Mol Genet 12:1907–1915. Escamilla MA, McInnes LA, Spesny M, Reus VI, Service SK, Shimayoshi N, Tyler DJ, Silva S, Molina J, Gallegos A, Meza L, Cruz ML, Batki S, Vinogradov S, Neylan T, Nguyen JB, Fournier E, Araya C, Barondes SH, Leon P, Sandkuijl LA, Freimer NB. 1999. Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18. Am J Hum Genet 64:1670–1678. Escamilla MA, McInnes LA, Service SK, Spesny M, Reus VI, Molina J, Gallegos A, Fournier E, Batki S, Neylan T, Matthews C, Vinogradov S, Roche E, Tyler DJ, Shimayoshi N, Mendez R, Ramirez R, Ramirez M, Araya C, Araya X, Leon PE, Sandkuijl LA, Freimer NB. 2001. Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18. Am J Med Genet 105:207–213. Escamilla MA, Ontiveros A, Nicolini H, Raventos H, Mendoza R, Medina R, Munoz R, Levinson D, Peralta JM, Dassori A, Almasy L. 2007. A genome-wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry. Am J Med Genet B Neuropsychiatr Genet 144:193–199. Etain B, Mathieu F, Rietschel M, Maier W, Albus M, McKeon P, Roche S, Kealey C, Blackwood D, Muir W, Bellivier F, Henry C, Dina C, Gallina S, Gurling H, Malafosse A, Preisig M, Ferrero F, Cichon S, Schumacher J, Ohlraun S, Borrmann-Hassenbach M, Propping P, Abou JR, Schulze TG, Marusic A, Dernovsek ZM, Giros B, Bourgeron T, Lemainque A, Bacq D, Betard C, Charon C, Nothen MM, Lathrop M, Leboyer M. 2006. Human Mutation DOI 10.1002/humu Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14. Mol Psychiatry 11: 685–694. Ewald H, Flint T, Kruse TA, Mors O. 2002a. A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22–21, 4p16, 6q14–22, 10q26 and 16p13.3. Mol Psychiatry 7:734–744. Ewald H, Flint TJ, Jorgensen TH, Wang AG, Jensen P, Vang M, Mors O, Kruse TA. 2002b. Search for a shared segment on chromosome 10q26 in patients with bipolar affective disorder or schizophrenia from the Faroe Islands. Am J Med Genet 114:196–204. Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE. 2003. Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 73:601–611. Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE. 2004. Genomewide linkage scan for bipolardisorder susceptibility loci among Ashkenazi Jewish families. Am J Hum Genet 75:204–219. Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, McGrath JA, Steel G, Nestadt G, Liang KY, Huganir RL, Valle D, Pulver AE. 2005. Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet 77:918–936. Faraone SV, Hwu HG, Liu CM, Chen WJ, Tsuang MM, Liu SK, Shieh MH, Hwang TJ, Ou-Yang WC, Chen CY, Chen CC, Lin JJ, Chou FH, Chueh CM, Liu WM, Hall MH, Su J, Van Eerdewegh P, Tsuang MT. 2006. Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22.3. Am J Psychiatry 163:1760–1766. Freimer NB, Reus VI, Escamilla MA, McInnes LA, Spesny M, Leon P, Service SK, Smith LB, Silva S, Rojas E, Gallegos A, Meza L, Fournier E, Baharloo S, Blankenship K, Tyler DJ, Batki S, Vinogradov S, Weissenbach J, Barondes SH, Sandkuijl LA. 1996. Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22–q23. Nat Genet 12:436–441. Fukui N, Muratake T, Kaneko N, Amagane H, Someya T. 2006. Supportive evidence for neuregulin 1 as a susceptibility gene for schizophrenia in a Japanese population. Neurosci Lett 396:117–120. Garner C, McInnes LA, Service SK, Spesny M, Fournier E, Leon P, Freimer NB. 2001. Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method. Am J Hum Genet 68:1061–1064. Garriock HA, Allen JJ, Delgado P, Nahaz Z, Kling MA, Carpenter L, Burke M, Burke W, Schwartz T, Marangell LB, Husain M, Erickson RP, Moreno FA. 2005. Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance. Mol Psychiatry 10: 976–977. Gasperoni TL, Ekelund J, Huttunen M, Palmer CG, Tuulio-Henriksson A, Lonnqvist J, Kaprio J, Peltonen L, Cannon TD. 2003. Genetic linkage and association between chromosome 1q and working memory function in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 116:8–16. Glatt CE, Carlson E, Taylor TR, Risch N, Reus VI, Schaefer CA. 2005. Response to Zhang et al. ( [155]2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16. Neuron 48:704–705. Gottesman II, Gould TD. 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K. 2006. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323. Green EK, Raybould R, Macgregor S, Gordon-Smith K, Heron J, Hyde S, Grozeva D, Hamshere M, Williams N, Owen MJ, O’Donovan MC, Jones L, Jones I, Kirov G, Craddock N. 2005. Operation of the schizophrenia HUMAN MUTATION 28(12), 1156^1170, 2007 susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. Arch Gen Psychiatry 62:642–648. Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjornsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR. 2003. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 35: 131–138. Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS, Read T, Murphy P, Blaveri E, McQuillin A, Petursson H, Curtis D. 2001. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 68: 661–673. Hamshere ML, Bennett P, Williams N, Segurado R, Cardno A, Norton N, Lambert D, Williams H, Kirov G, Corvin A, Holmans P, Jones L, Jones I, Gill M, O’Donovan MC, Owen MJ, Craddock N. 2005. Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. Arch Gen Psychiatry 62:1081–1088. Harrison PJ, Law AJ. 2006. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 60:132–140. Harvey M, Shink E, Tremblay M, Gagne B, Raymond C, Labbe M, Walther DJ, Bader M, Barden N. 2004. Support for the involvement of TPH2 gene in affective disorders. Mol Psychiatry 9:980–981. Helgason A, Nicholson G, Stefansson K, Donnelly P. 2003. A reassessment of genetic diversity in Icelanders: strong evidence from multiple loci for relative homogeneity caused by genetic drift. Ann Hum Genet 67: 281–297. Helgason A, Yngvadottir B, Hrafnkelsson B, Gulcher J, Stefansson K. 2005. An Icelandic example of the impact of population structure on association studies. Nat Genet 37:90–95. Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J, Parker A, Martin R, Levitzky S, Partonen T, Meyer J, Lonnqvist J, Peltonen L, Ekelund J. 2003. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 12:3151–3159. Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T, Cannon TD, Lonnqvist J, Peltonen L. 2005. A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia. Mol Psychiatry 10:1097–1103. Herzberg I, Jasinska A, Garcia J, Jawaheer D, Service S, Kremeyer B, Duque C, Parra MV, Vega J, Ortiz D, Carvajal L, Polanco G, Restrepo GJ, Lopez C, Palacio C, Levinson M, Aldana I, Mathews C, Davanzo P, Molina J, Fournier E, Bejarano J, Ramirez M, Ortiz CA, Araya X, Sabatti C, Reus V, Macaya G, Bedoya G, Ospina J, Freimer N, Ruiz-Linares A. 2006. Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31–34. Hum Mol Genet 15:3146–3153. Hong KS, McInnes LA, Service SK, Song T, Lucas J, Silva S, Fournier E, Leon P, Molina J, Reus VI, Sandkuijl LA, Freimer NB. 2004. Genetic mapping using haplotype and model-free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31-33. Am J Med Genet B Neuropsychiatr Genet 125:83–86. Hong CJ, Hou SJ, Yen FC, Liou YJ, Tsai SJ. 2006. Family-based association study between G72/G30 genetic polymorphism and schizophrenia. Neuroreport 17:1067–1069. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI. 2000. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175. Houwen RH, Baharloo S, Blankenship K, Raeymaekers P, Juyn J, Sandkuijl LA, Freimer NB. 1994. Genome screening by searching for shared 1167 segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nat Genet 8:380–386. Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R, Juvonen H, Kokko-Sahin ML, Vaisanen L, Mannila H, Lonnqvist J, Peltonen L. 1999. A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci. Am J Hum Genet 65:1114–1124. Ibrahim HM, Hogg AJ, Jr, Healy DJ, Haroutunian V, Davis KL, MeadorWoodruff JH. 2000. Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am J Psychiatry 157:1811–1823. Ingason A, Soeby K, Timm S, Wang AG, Jakobsen KD, Fink-Jensen A, Hemmingsen R, Berg RH, Werge T. 2006. No significant association of the 5’ end of neuregulin 1 and schizophrenia in a large Danish sample. Schizophr Res 83:1–5. Jones I, Jacobsen N, Green EK, Elvidge GP, Owen MJ, Craddock N. 2002. Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier’s disease. Mol Psychiatry 7: 424–427. Ke L, Qi ZY, Ping Y, Ren CY. 2006. Effect of SNP at position 40237 in exon 7 of the TPH2 gene on susceptibility to suicide. Brain Res 1122:24–26. Kelsoe JR, Spence MA, Loetscher E, Foguet M, Sadovnick AD, Remick RA, Flodman P, Khristich J, Mroczkowski-Parker Z, Brown JL, Masser D, Ungerleider S, Rapaport MH, Wishart WL, Luebbert H. 2001. A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 98:585–590. Ketter TA, Wang PW, Becker OV, Nowakowska C, Yang Y. 2004. Psychotic bipolar disorders: dimensionally similar to or categorically different from schizophrenia? J Psychiatr Res 38:47–61. Kim JW, Lee YS, Cho EY, Jang YL, Park DY, Choi KS, Jeun HO, Cho SH, Jang SY, Hong KS. 2006. Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population. Am J Med Genet B Neuropsychiatr Genet 141:281–286. Korostishevsky M, Kaganovich M, Cholostoy A, Ashkenazi M, Ratner Y, Dahary D, Bernstein J, Bening-Abu-Shach U, Ben Asher E, Lancet D, Ritsner M, Navon R. 2004. Is the G72/G30 locus associated with schizophrenia? Single nucleotide polymorphisms, haplotypes, and gene expression analysis. Biol Psychiatry 56:169–176. Korostishevsky M, Kremer I, Kaganovich M, Cholostoy A, Murad I, Muhaheed M, Bannoura I, Rietschel M, Dobrusin M, Bening-AbuShach U, Belmaker RH, Maier W, Ebstein RP, Navon R. 2006. Transmission disequilibrium and haplotype analyses of the G72/G30 locus: suggestive linkage to schizophrenia in Palestinian Arabs living in the North of Israel. Am J Med Genet B Neuropsychiatr Genet 141: 91–95. Lambert D, Middle F, Hamshere ML, Segurado R, Raybould R, Corvin A, Green E, O’Mahony E, Nikolov I, Mulcahy T, Haque S, Bort S, Bennett P, Norton N, Owen MJ, Kirov G, Lendon C, Jones L, Jones I, Holmans P, Gill M, Craddock N. 2005. Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22. Mol Psychiatry 10:831–841. [Erratum in: Mol Psychiatry 2006; 11:1140–1143.] Lerer B, Segman RH, Hamdan A, Kanyas K, Karni O, Kohn Y, Korner M, Lanktree M, Kaadan M, Turetsky N, Yakir A, Kerem B, Macciardi F. 2003. Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Mol Psychiatry 8:488–498. Levi A, Kohn Y, Kanyas K, Amann D, Pae CU, Hamdan A, Segman RH, Avidan N, Karni O, Korner M, Jun TY, Beckmann JS, Macciardi F, Lerer B. 2005. Fine mapping of a schizophrenia susceptibility locus at chromosome 6q23: increased evidence for linkage and reduced linkage interval. Eur J Hum Genet 13:763–771. Levinson DF, Holmans PA, Laurent C, Riley B, Pulver AE, Gejman PV, Schwab SG, Williams NM, Owen MJ, Wildenauer DB, Sanders AR, Nestadt G, Mowry BJ, Wormley B, Bauche S, Soubigou S, Ribble R, Nertney DA, Liang KY, Martinolich L, Maier W, Norton N, Williams H, Albus M, Carpenter EB, DeMarchi N, Ewen-White KR, Walsh D, Jay M, Deleuze JF, O’Neill FA, Papadimitriou G, Weilbaecher A, Lerer B, Human Mutation DOI 10.1002/humu 1168 HUMAN MUTATION 28(12), 1156^1170, 2007 O’Donovan MC, Dikeos D, Silverman JM, Kendler KS, Mallet J, Crowe RR, Walters M. 2002. No major schizophrenia locus detected on chromosome 1q in a large multicenter sample. Science 296:739–741. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, O’Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O’Donovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T.2003. Genome scan meta-analysis of schizophrenia and bipolar disorder. Part II: Schizophrenia. Am J Hum Genet 73:34–48. Li D, Collier DA, He L. 2006. Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet 15:1995–2002. Lin PI, McInnis MG, Potash JB, Willour VL, MacKinnon DF, Miao K, DePaulo JR, Zandi PP. 2005. Assessment of the effect of age at onset on linkage to bipolar disorder: evidence on chromosomes 18p and 21q. Am J Hum Genet 77:545–555. Lindholm E, Ekholm B, Shaw S, Jalonen P, Johansson G, Pettersson U, Sherrington R, Adolfsson R, Jazin E. 2001. A schizophrenia-susceptibility locus at 6q25, in one of the world’s largest reported pedigrees. Am J Hum Genet 69:96–105. Lindholm E, Aberg K, Ekholm B, Pettersson U, Adolfsson R, Jazin EE. 2004. Reconstruction of ancestral haplotypes in a 12-generation schizophrenia pedigree. Psychiatr Genet 14:1–8. Liu X, He G, Wang X, Chen Q, Qian X, Lin W, Li D, Gu N, Feng G, He L. 2004. Association of DAAO with schizophrenia in the Chinese population. Neurosci Lett 369:228–233. Liu YL, Fann CS, Liu CM, Chang CC, Wu JY, Hung SI, Liu SK, Hsieh MH, Hwang TJ, Chan HY, Chen JJ, Faraone SV, Tsuang MT, Chen WJ, Hwu HG. 2006. No association of G72 and D-amino acid oxidase genes with schizophrenia. Schizophr Res 87:15–20. Lopez VA, Detera-Wadleigh S, Cardona I, Kassem L, McMahon FJ. 2007. Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts. Biol Psychiatry 61: 181–186. Ma J, Qin W, Wang XY, Guo TW, Bian L, Duan SW, Li XW, Zou FG, Fang YR, Fang JX, Feng GY, Gu NF, St Clair D, He L. 2006. Further evidence for the association between G72/G30 genes and schizophrenia in two ethnically distinct populations. Mol Psychiatry 11:479–487. MacQueen GM, Hajek T, Alda M. 2005. The phenotypes of bipolar disorder: relevance for genetic investigations. Mol Psychiatry 10: 811–826. Marcheco-Teruel B, Flint TJ, Wikman FP, Torralbas M, Gonzalez L, Blanco L, Tan Q, Ewald H, Orntoft T, Kruse TA, Borglum AD, Mors O. 2006. A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba. Am J Med Genet B Neuropsychiatr Genet 141:833–843. Maziade M, Roy MA, Chagnon YC, Cliche D, Fournier JP, Montgrain N, Dion C, Lavallee JC, Garneau Y, Gingras N, Nicole L, Pires A, Ponton AM, Potvin A, Wallot H, Merette C. 2005. Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families. Mol Psychiatry 10:486–499. McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S, Rojas E, Spesny M, Baharloo S, Blankenship K, Peterson A, Tyler D, Shimayoshi N, Tobey C, Batki S, Vinogradov S, Meza L, Gallegos A, Fournier E, Smith LB, Barondes SH, Sandkuijl LA, Freimer NB. 1996. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci USA 93: 13060–13065. McInnes LA, Service SK, Reus VI, Barnes G, Charlat O, Jawahar S, Lewitzky S, Yang Q, Duong Q, Spesny M, Araya C, Araya X, Gallegos A, Meza L, Molina J, Ramirez R, Mendez R, Silva S, Fournier E, Batki SL, Mathews CA, Neylan T, Glatt CE, Escamilla MA, Luo D, Gajiwala P, Song T, Crook S, Nguyen JB, Roche E, Meyer JM, Leon P, Sandkuijl LA, Human Mutation DOI 10.1002/humu Freimer NB, Chen H. 2001. Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population. Proc Natl Acad Sci USA 98:11485–11490. McInnes LA, Lauriat TL. 2006. RNA metabolism and dysmyelination in schizophrenia. Neurosci Biobehav Rev 30:551–561. McInnis MG, Lan TH, Willour VL, McMahon FJ, Simpson SG, Addington AM, MacKinnon DF, Potash JB, Mahoney AT, Chellis J, Huo Y, SwiftScanlan T, Chen H, Koskela R, Stine OC, Jamison KR, Holmans P, Folstein SE, Ranade K, Friddle C, Botstein D, Marr T, Beaty TH, Zandi P, DePaulo JR. 2003. Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12. Mol Psychiatry 8:288–298. McQueen MB, Devlin B, Faraone SV, Nimgaonkar VL, Sklar P, Smoller JW, Abou JR, Albus M, Bacanu SA, Baron M, Barrett TB, Berrettini W, Blacker D, Byerley W, Cichon S, Coryell W, Craddock N, Daly MJ, DePaulo JR, Edenberg HJ, Foroud T, Gill M, Gilliam TC, Hamshere M, Jones I, Jones L, Juo SH, Kelsoe JR, Lambert D, Lange C, Lerer B, Liu J, Maier W, Mackinnon JD, McInnis MG, McMahon FJ, Murphy DL, Nothen MM, Nurnberger JI, Pato CN, Pato MT, Potash JB, Propping P, Pulver AE, Rice JP, Rietschel M, Scheftner W, Schumacher J, Segurado R, Van Steen K, Xie W, Zandi PP, Laird NM. 2005. Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. Am J Hum Genet 77: 582–595. Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF, Brown A, Petryshen TL, Kirby AN, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Azevedo MH, Kennedy JL, Daly MJ, Sklar P, Pato CN. 2004. Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotidepolymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet 74:886–897. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ. 2000. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9:1415–1423. Millar JK, James R, Christie S, Porteous DJ. 2005. Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci 30:477–484. Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B, Laprise C, Bouchard G, Plante M, Gobeil L, Shink E, Weissenbach J, Barden N. 1999. Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23–q24. Am J Med Genet 88:567–587. Muller-Oerlinghausen B, Berghofer A, Bauer M. 2002. Bipolar disorder. Lancet 359:241–247. Munafo MR, Thiselton DL, Clark TG, Flint J. 2006. Association of the NRG1 gene and schizophrenia: a meta-analysis. Mol Psychiatry 11: 539–546. Nylander PO, Beckman L. 1991. Population studies in northern Sweden. XVII. Estimates of Finnish and Saamish influence. Hum Hered 41:157–167. Ostrer H. 2001. A genetic profile of contemporary Jewish populations. Nat Rev Genet 2:891–898. Pato CN, Azevedo MH, Pato MT, Kennedy JL, Coelho I, Dourado A, Macedo A, Valente J, Ferreira CP, Madeira J, Gago dC, Moniz M, Correia C. 1997. Selection of homogeneous populations for genetic study: the Portugal genetics of psychosis project. Am J Med Genet 74:286–288. Pato CN, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Verner A, Hudson TJ, Morley CP, Kennedy JL, Azevedo MH, Daly MJ, Sklar P. 2004. Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11. Am J Med Genet 127B:30–34. Paunio T, Ekelund J, Varilo T, Parker A, Hovatta I, Turunen JA, Rinard K, Foti A, Terwilliger JD, Juvonen H, Suvisaari J, Arajarvi R, Suokas J, Partonen T, Lonnqvist J, Meyer J, Peltonen L. 2001. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals HUMAN MUTATION 28(12), 1156^1170, 2007 susceptibility loci on chromosomes 2q and 5q. Hum Mol Genet 10:3037–3048. Paunio T, Tuulio-Henriksson A, Hiekkalinna T, Perola M, Varilo T, Partonen T, Cannon TD, Lonnqvist J, Peltonen L. 2004. Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q. Hum Mol Genet 13:1693–1702. Peltonen L, Palotie A, Lange K. 2000. Use of population isolates for mapping complex traits. Nat Rev Genet 1:182–190. Porteous DJ, Thomson P, Brandon NJ, Millar JK. 2006. The genetics and biology of DISC1—an emerging role in psychosis and cognition. Biol Psychiatry 60:123–131. Potash JB, Zandi PP, Willour VL, Lan TH, Huo Y, Avramopoulos D, Shugart YY, MacKinnon DF, Simpson SG, McMahon FJ, DePaulo JR Jr, McInnis MG. 2003. Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder. Am J Psychiatry 160:680–686. Pulver AE, Lasseter VK, Kasch L, Wolyniec P, Nestadt G, Blouin JL, Kimberland M, Babb R, Vourlis S, Chen H. 1995. Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. Am J Med Genet 60:252–260. Puri V, McQuillin A, Choudhury K, Datta S, Pimm J, Thirumalai S, Krasucki R, Lawrence J, Quested D, Bass N, Moorey H, Morgan J, Punukollu B, Kandasami G, Curtis D, Gurling H. 2007. Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene. Biol Psychiatry 61:873–879. Ribas G, Gonzalez-Neira A, Salas A, Milne RL, Vega A, Carracedo B, Gonzalez E, Barroso E, Fernandez LP, Yankilevich P, Robledo M, Carracedo A, Benitez J. 2006. Evaluating HapMap SNP data transferability in a large-scale genotyping project involving 175 cancerassociated genes. Hum Genet 118:669–679. Riley B, Kendler KS. 2006. Molecular genetic studies of schizophrenia. Eur J Hum Genet 14:669–680. Sachs NA, Sawa A, Holmes SE, Ross CA, DeLisi LE, Margolis RL. 2005. A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry 10:758–764. Schulze TG, Ohlraun S, Czerski PM, Schumacher J, Kassem L, Deschner M, Gross M, Tullius M, Heidmann V, Kovalenko S, Jamra RA, Becker T, Leszczynska-Rodziewicz A, Hauser J, Illig T, Klopp N, Wellek S, Cichon S, Henn FA, McMahon FJ, Maier W, Propping P, Nothen MM, Rietschel M. 2005. Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes. Am J Psychiatry 162:2101–2108. Schumacher J, Jamra RA, Freudenberg J, Becker T, Ohlraun S, Otte AC, Tullius M, Kovalenko S, Bogaert AV, Maier W, Rietschel M, Propping P, Nothen MM, Cichon S. 2004. Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry 9:203–207. Schwab SG, Eckstein GN, Hallmayer J, Lerer B, Albus M, Borrmann M, Lichtermann D, Ertl MA, Maier W, Wildenauer DB. 1997. Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis. Mol Psychiatry 2:156–160. Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger JI, Jr, Craddock N, DePaulo JR, Baron M, Gershon ES, Ekholm J, Cichon S, Turecki G, Claes S, Kelsoe JR, Schofield PR, Badenhop RF, Morissette J, Coon H, Blackwood D, McInnes LA, Foroud T, Edenberg HJ, Reich T, Rice JP, Goate A, McInnis MG, McMahon FJ, Badner JA, Goldin LR, Bennett P, Willour VL, Zandi PP, Liu J, Gilliam C, Juo SH, Berrettini WH, Yoshikawa T, Peltonen L, Lonnqvist J, Nothen MM, Schumacher J, Windemuth C, Rietschel M, Propping P, Maier W, Alda M, Grof P, Rouleau GA, Del Favero J, Van Broeckhoven C, Mendlewicz J, Adolfsson R, Spence MA, Luebbert H, Adams LJ, Donald JA, Mitchell PB, Barden N, Shink E, Byerley W, Muir W, Visscher PM, Macgregor S, Gurling H, Kalsi G, McQuillin A, Escamilla MA, Reus VI, Leon P, Freimer NB, Ewald H, Kruse TA, Mors O, Radhakrishna U, 1169 Blouin JL, Antonarakis SE, Akarsu N. 2003. Genome scan meta-analysis of schizophrenia and bipolar disorder. Part III: Bipolar disorder. Am J Hum Genet 73:49–62. Service SK, Ophoff RA, Freimer NB. 2001. The genome-wide distribution of background linkage disequilibrium in a population isolate. Hum Mol Genet 10:545–551. Service S, DeYoung J, Karayiorgou M, Roos JL, Pretorious H, Bedoya G, Ospina J, Ruiz-Linares A, Macedo A, Palha JA, Heutink P, Aulchenko Y, Oostra B, Van Duijn C, Jarvelin MR, Varilo T, Peddle L, Rahman P, Piras G, Monne M, Murray S, Galver L, Peltonen L, Sabatti C, Collins A, Freimer N. 2006. Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nat Genet 38:556–560. Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J, Laval SH, Vita A, De Hert M, Cardon LR, Crow TJ, Sherrington R, DeLisi LE. 1998. A genome-wide search for schizophrenia susceptibility genes. Am J Med Genet 81:364–376. Shih R, Belmonte P, Zandi P. 2004. A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry 16:260–283. Shink E, Morissette J, Barden N. 2003. Genetic heterogeneity in a very large bipolar affective disorder pedigree from Quebec. Am J Med Genet B Neuropsychiatr Genet 119:65–68. Shink E, Harvey M, Tremblay M, Gagne B, Belleau P, Raymond C, Labbe M, Dube MP, Lafreniere RG, Barden N. 2005a. Analysis of microsatellite markers and single nucleotide polymorphisms in candidate genes for susceptibility to bipolar affective disorder in the chromosome 12Q24.31 region. Am J Med Genet B Neuropsychiatr Genet 135:50–58. Shink E, Morissette J, Sherrington R, Barden N. 2005b. A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12. Mol Psychiatry 10:545–552. Sklar P, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Verner A, Hudson TJ, Morley CP, Kennedy JL, Azevedo MH, Lander E, Daly MJ, Pato CN. 2004. Genome-wide scan in Portuguese Island families identifies 5q31–5q35 as a susceptibility locus for schizophrenia and psychosis. Mol Psychiatry 9:213–218. Smith EM, Wang X, Littrell J, Eckert J, Cole R, Kissebah AH, Olivier M. 2006. Comparison of linkage disequilibrium patterns between the HapMap CEPH samples and a family-based cohort of Northern European descent. Genomics 88:407–414. Smoller JW, Finn CT. 2003. Family, twin, and adoption studies of bipolar disorder. Am J Med Genet 123C:48–58. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans HJ. 1990. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336:13–16. Stankovich J, Cox CJ, Tan RB, Montgomery DS, Huxtable SJ, Rubio JP, Ehm MG, Johnson L, Butzkueven H, Kilpatrick TJ, Speed TP, Roses AD, Bahlo M, Foote SJ. 2006. On the utility of data from the International HapMap Project for Australian association studies. Hum Genet 119:220–222. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K. 2002. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892. Straub RE, MacLean CJ, O’Neill FA, Walsh D, Kendler KS. 1997. Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families. Mol Psychiatry 2:148–155. The International HapMap Consortium. 2003. The International HapMap Project. Nature 426:789–796. The International HapMap Consortium. 2005. A haplotype map of the human genome. Nature 437:1299–1320. Thomson PA, Christoforou A, Morris SW, Adie E, Pickard BS, Porteous DJ, Muir WJ, Blackwood DH, Evans KL. 2007. Association of Neuregulin 1 Human Mutation DOI 10.1002/humu 1170 HUMAN MUTATION 28(12), 1156^1170, 2007 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. Mol Psychiatry 12:94–104. Van Den Bogaert A, De Zutter S, Heyrman L, Mendlewicz J, Adolfsson R, Van Broeckhoven C, Del Favero J. 2005. Response to Zhang et al (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16. Neuron 48:704–706. Van Den Bogaert A, Sleegers K, De Zutter S, Heyrman L, Norrback KF, Adolfsson R, Van Broeckhoven C, Del Favero J. 2006. Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population. Arch Gen Psychiatry 63:1103–1110. Venken T, Claes S, Sluijs S, Paterson AD, Van Duijn C, Adolfsson R, Del Favero J, Van Broeckhoven C. 2005. Genomewide scan for affective disorder susceptibility Loci in families of a northern Swedish isolated population. Am J Hum Genet 76:237–248. Venken T, Alaerts M, Souery D, Goossens D, Sluijs S, Navon R, Van Broeckhoven C, Mendlewicz J, Del-Favero J, Claes S. 2007. Chromosome 10q harbours a susceptibility locus for bipolar disorder in Ashkenazi Jewish families. Mol Psychiatry (Epub ahead of print). Walss-Bass C, Raventos H, Montero AP, Armas R, Dassori A, Contreras S, Liu W, Medina R, Levinson DF, Pereira M, Leach RJ, Almasy L, Escamilla MA. 2006. Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population. Acta Psychiatr Scand 113:314–321. Walter L, Dinh T, Stella N. 2004. ATP induces a rapid and pronounced increase in 2-arachidonoylglycerol production by astrocytes, a response limited by monoacylglycerol lipase. J Neurosci 24:8068–8074. Wildenauer DB, Schwab SG. 1999. Chromosomes 8 and 10 workshop. Am J Med Genet 88:239–243. Willer CJ, Scott LJ, Bonnycastle LL, Jackson AU, Chines P, Pruim R, Bark CW, Tsai YY, Pugh EW, Doheny KF, Kinnunen L, Mohlke KL, Valle TT, Bergman RN, Tuomilehto J, Collins FS, Boehnke M. 2006. Tag SNP selection for Finnish individuals based on the CEPH Utah HapMap database. Genet Epidemiol 30:180–190. Williams NM, Norton N, Williams H, Ekholm B, Hamshere ML, Lindblom Y, Chowdari KV, Cardno AG, Zammit S, Jones LA, Murphy KC, Sanders RD, McCarthy G, Gray MY, Jones G, Holmans P, Nimgaonkar V, Adolfson R, Osby U, Terenius L, Sedvall G, O’Donovan MC, Owen MJ. 2003. A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 73:1355–1367. Human Mutation DOI 10.1002/humu Williams NM, Green EK, Macgregor S, Dwyer S, Norton N, Williams H, Raybould R, Grozeva D, Hamshere M, Zammit S, Jones L, Cardno A, Kirov G, Jones I, O’Donovan MC, Owen MJ, Craddock N. 2006. Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder. Arch Gen Psychiatry 63:366–373. Wood LS, Pickering EH, Dechairo BM. 2007. Significant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia. Biol Psychiatry 61: 1195–1199. Xu B, Wratten N, Charych EI, Buyske S, Firestein BL, Brzustowicz LM. 2005. Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder. PLoS Med 2:e263. Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG. 2005. Loss-offunction mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16. Zheng Y, Li H, Qin W, Chen W, Duan Y, Xiao Y, Li C, Zhang J, Li X, Feng G, He L. 2005. Association of the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase gene with schizophrenia in the Chinese Han population. Biochem Biophys Res Commun 328: 809–815. Zhou Z, Peters EJ, Hamilton SP, McMahon F, Thomas C, McGrath PJ, Rush J, Trivedi MH, Charney DS, Roy A, Wisniewski S, Lipsky R, Goldman D. 2005a. Response to Zhang et al. ( [155]2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45:11–16. Neuron 48:702–703. Zhou Z, Roy A, Lipsky R, Kuchipudi K, Zhu G, Taubman J, Enoch MA, Virkkunen M, Goldman D. 2005b. Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations. Arch Gen Psychiatry 62:1109–1118. Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R, Moller HJ, Bondy B, Ackenheil M. 2004a. SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 9:1030–1036. Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M. 2004b. Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 56:581–586.