Vsevolod Rozanov

The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress

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.

Depression in suicidal males: genetic risk variants in the CRHR1 gene

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.

Nature and nurture in suicidal behavior, the role of genetics: some novel findings concerning personality traits and neural conduction.

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.

The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt

BackgroundSerotonergic 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.MethodsThe 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.ResultsNo 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).ConclusionThe 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 attempt and basic mechanisms in neural conduction: Relationships to the SCN8A and VAMP4 genes

Family and twin studies show that genetic variation influences suicidal behavior, but do not indicate specific genes. We investigated the relationship between genetic variation and suicide attempt by screening 250 genetic markers using transmission disequilibrium test (TDT) analysis. Analysis of 77 triplets (suicide attempters and both their parents), indicated that gene‐variants in, or adjacent to, the sodium channel, voltage gated, type VIII, alpha polypeptide (SCN8A) (P = 0.008), vesicle‐associated membrane protein 4 (VAMP4) (P = 0.004), and prenylated Rab acceptor 1 (RABAC1) (P = 0.006) genes are over‐transmitted in suicide attempt. Replication in a separate sample, consisting of 190 triplets, confirmed the exploratory data for the SCN8A (P = 0.005) and VAMP4 (P = 0.019) genes, but failed to confirm the data for the RABAC1 gene. Our results indicate that genetic variation in the SCN8A and VAMP4 genes may contribute to risk for suicide attempt, possibly through alterations in neural conduction.

Association of the serotonin transporter promotor polymorphism with suicide attempters with a high medical damage.

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 (chi2=9.054, df=1, p=0.0026). The results suggest that the S-allele may predispose for suicidal behavior characterized by high determination.

Successful model of suicide prevention in the Ukraine military environment

The article deals with the problem of suicidal behavior in the Ukraine military environment and gives an example of the successful prevention approach. The model of prevention is based on (1) education of the responsible officers, (2) training of the representatives of the most vulnerable risk groups, and (3) follow-up procedures based on distribution of pocket books for soldiers, educational booklets, and sets of helpful materials for officers. One of the main conclusions is that the prevention activity must be organized as a continuum of actions, seminars, consultations, and materials distribution.

Genetic variation in the hypothalamic-pituitary-adrenocortical axis regulatory factor, T-box 19, and the angry/hostility personality trait

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.

Evidence-based national suicide prevention taskforce in Europe : a consensus position paper

Gil Zalsman, Keith Hawton, Danuta Wasserman, Kees van Heeringen, Ella Arensman, Marco Sarchiapone, Vladimir Carli, Cyril Höschl, Petr Winkler, Judit Balazs, György Purebl, Jean Pierre Kahn, Pilar Alejandra Sáiz, Julio Bobes, Doina Cozman, Ulrich Hegerl, Elmārs Rancāns, Gergö Hadlaczky, Chantal Van Audenhove, Haggy Hermesh, Merike Sisask, Armen Melik Peschayan, Nestor Kapusta, Virginja Adomaitiene, Vesta Steibliene, Iwowa Kosiewska, Vsevolod Rozanov, Philp Courtet, Joseph Zohar, European Evidence-Based Suicide Prevention Program [EESPP] Group by the Expert Platform on Mental Health, Focus on Depression

CS05-01 Core symposium: Suicide across Europe. Epidemiology of completed suicide in Europe: Main tendencies and trends

Suicide is well represented in the WHO mortality databases, providing the opportunity to study and discuss how ethno-genetic, cultural, religious, economical and political issues may influence suicide rates in different regions and countries. The problem is that all these factors act together and often with contrasting effect. Suicide rates in Europe vary widely - from about 30 per 100000 of population in Lithuania, Russian Federation, Belarus and Kazakhstan to about 1-2 per 100000 in Cyprus, Azerbaijan, Georgia, Armenia and Greece. It is possible to see from the map, that suicide rates diminish when moving from North to South and from East to West. This may be discussed within the so called “Finno-Ugrian hypothesis”. Gender is one of the issues most widely discussed in suicidal behavior. Across Europe males commit suicides 3-5 times more often than females. Dramatic changes in suicide rates on the post-soviet space are associated with male suicides, while female suicides remained almost unchanged. One explaination is a higher susceptibility of males to socio-economic stress while females seem to be more protected. There is a general rule that suicide rates go up with increasing age. In countries like Ukraine, suicide is significantly higher in rural than in urban areas. Other factors influencing suicides are seasonality, alcohol and substance abuse in the given population. Life-stress and its equivalents seem to be very important, as many other conditions (like cardiovascular and cerebrovascular diseases and accidents) have the same pattern as suicide when studying mortality rates across Europe.