Marcus Sokolowski

Suicidal behaviors (SB) may be regarded as the outmost consequence of mental illnesses, or as a distinct entity per se. Regardless, the consequences of SB are very large to both society and affected individuals. The path leading to SB is clearly a complex one involving interactions between the subject's biology and environmental influences throughout life. With the aim to generate a representative and diversified overview of the different neurobiological components hypothesized or shown implicated across the entire SB field up to date by any approach, we selected and compiled a list of 212 gene symbols from the literature. An increasing number of novel gene (products) have been introduced as candidates, with half being implicated in SB in only the last 4 years. These candidates represent different neuro systems and functions and might therefore be regarded as competing or redundant explanations. We then adopted a unifying approach by treating them all as parts of the same meta-system, using bioinformatic tools. We present a network of all components connected by physical protein-protein interactions (the SB interactome). We proceeded by exploring the differences between the highly connected core (~30% of the candidate genes) and its peripheral parts, observing more functional homogeneity at the core, with multiple signal transduction pathways and actin-interacting proteins connecting a subset of receptors in nerve cell compartments as well as development/morphology phenotypes and the stress-sensitive synaptic plasticity processes of long term potentiation/depression. We suggest that SB neurobiology might also be viewed as one meta-system and perhaps be explained as intrinsic unbalances acting within the core or as imbalances arising between core and specific peripheral components.

Expression levels of human papillomavirus type 1 late genes are determined in part by an AU-rich inhibitory sequence in the 3' untranslated region on the late mRNAs. Fine mapping of the AU rich inhibitory sequence revealed that it mapped to a 57 nucleotide sequence, consisting of an AU-rich region containing two AUUUA motifs and a U-rich region containing three UUUUU motifs. An internal deletion showed that the U-rich region was required for inhibition. Point mutations in the AUUUA- and UUUUU-motifs inactivated the inhibitory sequence. Analysis of the stability of mRNAs containing the AU-rich sequence in sense or anti-sense orientation showed that mRNAs containing the AU-rich sequence in sense orientation had reduced half life. Analysis of RNA-protein interactions revealed that binding to the inhibitory sequence of three poly(U) binding proteins (38, 44 and 46 kDa) correlated with inhibition and that the same proteins bind to the AU-rich mRNA instability element in the 3' untranslated region on the human c-fos mRNA. We speculate that the human papillomavirus late mRNAs, produced from several hundred copies of the virus genome present in infected cells, compete with the c-fos mRNAs for destabilizing cellular factors and that this may lead to elevated Fos protein levels in human papillomavirus infected cells.

A 3-day Nobel Conference entitled 'The role of genetics in promoting suicide prevention and the mental health of the population' was held at the Nobel Forum, Karolinska Institute (KI) in Stockholm, Sweden, during 8-10 June 2009. The conference was sponsored by the Nobel Assembly for Physiology or Medicine and organized by the National Prevention for Suicide and Mental Ill-Health and the Center for Molecular Medicine at KI. The program consisted of 19 invited presentations, covering the genetic basis of mood/psychotic disorders and substance abuse in relation to suicide, with topics ranging from cellular-molecular mechanisms to (endo)phenotypes of mental disorders at the level of the individual and populations. Here, we provide an overview based on the highlights of what was presented.

The risk of suicide, which causes about 1 million deaths each year, is considered to augment as the levels of stress increases. Dysregulation in the stress response of the hypothalamic-pituitary-adrenocortical (HPA) axis, involving the corticotrophin-releasing hormone (CRH) and its main receptor (CRHR1), is associated with depression, frequent among suicidal males. Here we have analyzed single nucleotide polymorphisms (SNPs) in these genes, in family trios with suicide attempter offspring (n = 542), by using the transmission disequilibrium test both in a two-staged screening/replication sample design and in detailed reanalysis in the entire sample. Stratification based on the levels of lifetime stress showed reproducible association and linkage of an SNP in the CRHR1 gene (rs4792887) to suicide attempters exposed to low levels of stress (P = 0.002), among whom most males were depressed (P = 0.001). The identified allele may represent a part of the genetic susceptibility for suicidality by increasing HPA axis activity upon exposure to low levels of stress.

Neurotic personality traits are important factors in several psychiatric disorders and suicidal behavior. Here, we have investigated the existence of potential relationships between neurotic personality traits and genetic variation. Non-suicidal parents derived from trios (suicide attempter and both parents) and non-suicidal volunteers, examined by the Neuroticism, Extraversion and Openness (NEO) Personality Inventory – Revised (NEO PI-R), were divided into screening and replication samples. The screening sample (n= 127) was used to select potential relationships between neurotic personality traits and genetic variation among 130 single nucleotide polymorphisms (SNPs). Screening (analysis of variance) with regard to the personality dimension neuroticism indicated potential relationships at three different loci. More detailed analysis of these three SNPs at NEO PI-R facet level indicated four potential relationships. T-test analysis in the replication sample (n= 617) was used to retest the relationships indicated during screening. One of those relationships was confirmed in the replication sample (P= 0.0052; Bonferroni correction), indicating that genetic variation at the human T-box 19 (TBX19) locus is related to the personality trait angry/hostility. Furthermore, using analysis of haplotypes among trios by transmission disequilibrium test and its extension, the family-based association test, overtransmission of a haplotype GAC at the TBX19 locus was associated with increased angry/hostility scores among suicide attempters (P= 0.009; Bonferroni correction). This is to our knowledge the first report on the association of the angry hostility personality trait with genetic variation at the TBX19 locus, an important regulator of the hypothalamic–pituitary–adrenocortical axis.

Suicide affects about one million people each year, a phenomenon characterized by heterogeneous and complex causes. Often environmental factors such as negative life events may act as a significant contributor to suicidal behavior. However, in many cases the exposure to the same environmental stress does not result in increased suicidality. It is now well established that there is also a substantial genetic contribution to suicidal behavior. Here, functional and association studies which implicate specific genes in psychological traits and environmental factors are discussed, interactions which are related to completed suicide or suicide attempt, and our novel findings which need replication are presented. We found that genetic variation in the noradrenergic tyrosine hydroxylase gene was associated with the angry/hostility personality trait and vulnerability to stress. Similarly, we recently discovered that genetic variation in components of the stress-related hypothalamic pituitary adrenocortical axis, T-box 19 and corticotropin releasing hormone receptor 1, showed association and linkage to high anger/hostility in and male depression the suicidal offspring, respectively. Further results from our studies have revealed that genetic variation in genes with roles in basal mechanisms of neural conduction, voltage-gated sodium channel type VIII alpha and vesicle-associated membrane 4 protein, showed association and linkage among suicide attempters. Additionally, we have results which give support to the findings of others, implicating the serotonin transporter and serotonin receptor 1A in suicidal behavior. Our future studies aim at identifying and resolving complex patterns and mechanisms of neurobiological gene-environment interactions, which may contribute to suicide.

Background Serotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters. Methods The involvement of the implicated G-allele of the 5-HTR1A C(-1019)G polymorphism (rs6295) was analyzed with the transmission disequilibrium test (TDT) in a sample of 272 suicide attempter families. Results No overtransmission of the G-allele was found in the entire sample of suicide attempters (p = 0.1460; n = 272 trios). However, a strong trend for overtransmission of the G-allele was observed in a sub-sample selected for a high level of previous traumatic and/or stressful life events prior to the suicide attempt (p = 0.0630, two-tail; n = 94 trios). Conclusion The current results show that variation at the rs6295 polymorphism of the HTR1A gene is not associated with suicide attempts generally. However, the results indicate a possible role of the G-allele in suicidal behavior in connection with high exposure to traumatic and/or stressful life events, which is in need of future investigation.

Suicide is a major public health problem in the WHO European Region accounting for over 150,000 deaths per year.Acute intervention should start immediately in order to keep the patient alive.An underlying psychiatric disorder is present in up to 90% of people who completed suicide. Comorbidity with depression, anxiety, substance abuse and personality disorders is high. In order to achieve successful prevention of suicidality, adequate diagnostic procedures and appropriate treatment for the underlying disorder are essential.Existing evidence supports the efficacy of pharmacological treatment and cognitive behavioural therapy (CBT) in preventing suicidal behaviour. Some other psychological treatments are promising, but the supporting evidence is currently insufficient. Studies show that antidepressant treatment decreases the risk for suicidality among depressed patients. However, the risk of suicidal behaviour in depressed patients treated with antidepressants exists during the first 10–14 days of treatment, which requires careful monitoring. Short-term supplementary medication with anxiolytics and hypnotics in the case of anxiety and insomnia is recommended. Treatment with antidepressants of children and adolescents should only be given under supervision of a specialist. Long-term treatment with lithium has been shown to be effective in preventing both suicide and attempted suicide in patients with unipolar and bipolar depression. Treatment with clozapine is effective in reducing suicidal behaviour in patients with schizophrenia. Other atypical antipsychotics are promising but more evidence is required.Multidisciplinary treatment teams including psychiatrist and other professionals such as psychologist, social worker, and occupational therapist are always preferable, as integration of pharmacological, psychological and social rehabilitation is recommended especially for patients with chronic suicidality.The suicidal person independently of age should always be motivated to involve family in the treatment.Psychosocial treatment and support is recommended, as the majority of suicidal patients have problems with relationships, work, school and lack functioning social networks.A secure home, public and hospital environment, without access to suicidal means is a necessary strategy in suicide prevention. Each treatment option, prescription of medication and discharge of the patient from hospital should be carefully evaluated against the involved risks.Training of general practitioners (GPs) is effective in the prevention of suicide. It improves treatment of depression and anxiety, quality of the provided care and attitudes towards suicide. Continuous training including discussions about ethical and legal issues is necessary for psychiatrists and other mental health professionals.

Serotonergic neurotransmission has been implicated in suicidal behavior, including inconsistent results concerning the serotonin transporter promoter polymorphism (5-HTTLPR). Here, we analyzed the 5-HTTLPR in suicide attempters (n = 85). Comparing the presence of SS with SL + LL genotypes showed a significantly higher prevalence of the SS genotype in suicide attempters with high medical damage scores (χ2 = 9.054, df = 1, p = 0.0026). The results suggest that the S-allele may predispose for suicidal behavior characterized by high determination.

Dysregulation in the stress response of the hypothalamic–pituitary–adrenal axis, involving the corticotrophin-releasing hormone and its main receptor (CRHR1), is considered to play a major role in depression and suicidal behavior. To comprehensively map the genetic variation in CRHR1 in relation to suicidality and depression, as a follow-up to our initial report on SNP rs4792887, we analyzed six new single nucleotide polymorphisms (SNPs), in an extended sample of family trios (n = 672) with suicide attempter offspring, by using family-based association tests. The minor T-allele of exonic SNP rs12936511, not previously studied in the context of psychiatric disorders and suicidal behaviors, was significantly transmitted to suicidal males with increased Beck Depression Inventory (BDI) scores (n = 347; P = 0.0028). We found additional evidence of association and linkage with increased BDI scores among suicidal males with an additional SNP, located proximally to the index SNP rs4792887, as well as with two distal SNPs, which were correlated with index SNP rs4792887. Analysis of haplotypes showed that each of the risk alleles segregated onto three separate haplotypes, whereas a fourth ‘nonrisk’ haplotype (‘CGC’) contained none of the risk alleles and was preferentially transmitted to suicidal males with lowered BDI scores (P = 0.0007). The BDI scores among all suicidal males, who carried a homozygous combination of any of the three risk haplotypes (non-CGC/non-CGC; n = 160), were significantly increased (P = 0.000089) compared with suicidal male CGC carriers (n = 181). Thus, while the characteristics of the suicide female attempters remained undetermined, the male suicidal offspring had increased depression intensity related to main genetic effects by exonic SNP rs12936511 and homozygous non-CGC haplotypes.