Suicidal behaviours, which range from suicidal ideation to suicide attempts and completed suicide, represent a fatal dimension of mental ill-health. The involvement of genetic risk factors in suicidal behaviour is supported by family, twin, and adoption studies. The aim of this paper is to review recent genetic association studies in suicidal behaviours including (i) case-control studies, (ii) family-based association studies and (iii) genome-wide association studies (GWAS). Various studies on genetic associations have tended to suggest that a number of genes (e.g., tryptophan hydroxylase, serotonin receptors and transporters or brain-derived neurotrophic factors) are linked to suicidal behaviours, but these findings are not consistently supported by the results obtained. Although the candidate-gene approach is useful, it is hampered by the present state of knowledge concerning the pathophysiology of diseases. Interpretations of GWAS results are mostly hindered by a lack of annotation describing the functions of most variation throughout the genome. Association studies have addressed a wide range of SNPs in numerous genes. We have included 104 such studies, of which 10 are family-based association studies and 11 are GWAS studies. Numerous meta-analyses of case-control studies have shown significant associations of suicidal behaviour with variants in the serotonin transporter gene (5-HTT or SLC6A4) and the tryptophane hydroxylase1 gene (TPH1), but others report contradictory results. The gene encoding brain-derived neurotrophic factor (BDNF) and its receptor (NTRK2) are also promising candidates. Only two of the GWAS studies showed any significant associations. Several pathways are mentioned in an attempt to understand the lack of reproducibility and the disappointing results. Consequently, we review and discuss here the following aspects: (i) sample characteristics and confounding factors; (ii) statistical limits; (iii) gene-gene interactions; (iv) gene, environment and by time interactions; and (v) technological and theoretical limits. Keywords: association study, genetics of suicide, suicidal behaviour, single nucleotide polymorphism

/pdf/genetic-association-studies-of-suicidal-behavior-a-review-of-2qkkj3715i.pdf

Genetic Association Studies of Suicidal Behavior: A Review of the Past 10 Years, Progress, Limitations, and Future Directions.

The role of the serotonergic system at the interface of aggression and suicide.

Serotonin (5-HT) modulates the stress response by interacting with the hormonal hypothalamic-pituitary-adrenal (HPA) axis and neuronal sympathetic nervous system (SNS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. While TPH2 genetic variance has been linked to numerous behavioral traits and disorders, findings on TPH2 gene expression have not only reinforced, but also provided new insights into, the long-recognized but not yet fully understood 5-HT-stress interaction. In this review, we summarize advances in TPH2 expression regulation and its relevance to the stress response and clinical implications. Particularly, based on findings on rhesus monkey TPH2 genetics and other relevant literature, we propose that: 1) upon activation of adrenal cortisol secretion, the cortisol surge induces TPH2 expression and de novo 5-HT synthesis; 2) the induced 5-HT in turn inhibits cortisol secretion by modulating the adrenal sensitivity to ACTH via the suprachiasmatic nuclei (SCN)-SNS-adrenal system, such that it contributes to the feedback inhibition of cortisol production; 3) basal TPH2 expression or 5-HT synthesis, as well as early-life experience, influence basal cortisol primarily via the hormonal HPA axis; and 4) 5′- and 3′-regulatory polymorphisms of TPH2 may differentially influence the stress response, presumably due to their differential roles in gene expression regulation. Our increasing knowledge of TPH2 expression regulation not only helps us better understand the 5-HT-stress interaction and the pathophysiology of neuropsychiatric disorders, but also provides new strategies for the treatment of stress-associated diseases.

Advances in tryptophan hydroxylase-2 gene expression regulation: New insights into serotonin–stress interaction and clinical implications†‡

TPH2 polymorphisms across the spectrum of psychiatric morbidity: A systematic review and meta-analysis.

Objective: To analyze the factors associated with recent suicide attempts including socio-demographic and clinical characteristics in major depressive disorder (MDD) patients in China. Methods: The data were from a nationwide sample from 13 major psychiatric hospitals or the psychiatric units of general hospitals in China, from September 1, 2010 to February 28, 2011. Melancholic features and suicide attempts in the past month were defined according to the melancholic feature module and the suicide module of the Mini International Neuropsychiatric Interview (MINI). Socio-demographic and clinical characteristics were compared between MDD patients with and without recent suicide attempts. Further analyses regarding the factors associated with recent suicide attempts in MDD patients were performed via multivariate logistic regression analysis. Results: Among 1,172 MDD patients, 57 (4.9%) were reported to have made a suicide attempt in the past month. Compared to the MDD patients without recent suicide attempt, significantly higher percentage of patients in the recent suicide attempters group had previous suicide attempts (χ2 = 171.861, p < 0.001) and depressive episodes with melancholic features (χ2 = 22.837, p < 0.001). Logistic regression analysis indicated that previous suicide attempts (OR = 20.81, 95% CI: 11.12-38.94, p < 0.001) and depressive episodes with melancholic features (OR = 4.43, 95% CI: 2.09-9.43, p < 0.001) were independently associated with recent suicide attempts in MDD patients. Limitations: Cross-sectional design, retrospective recall of suicide attempt data. Conclusion: Recent suicide attempts are associated with melancholic features and previous suicide attempts in MDD patients in China. These data may help clinicians to identify MDD patients at high risk of suicide attempt behavior.

/pdf/risk-factors-for-recent-suicide-attempts-in-major-depressive-4kdk32m1k0.pdf

Risk Factors for Recent Suicide Attempts in Major Depressive Disorder Patients in China: Results From a National Study.

OBJECTIVE To understand the environmental risk factors on attempted suicide in patients with major depression, and to study the interaction between factors as single nucleotide polymorphism(SNP) of TPH2 gene rs7305115 associated to attempted suicide in major depression. METHODS Paired case-control study on 215 suicide attempters with major depression (92 male, 123 female) and molecular biological techniques were used to study the relation between TPH2 gene rs7305115 SNP,interrelated environmental factors and the rate of attempted suicide. Controls were paired with cases according to the same gender, similar age (no more than 3 years) and from the same district. RESULTS There were remarkably significant differences in gene types and gene frequency between case and control groups (P < 0.001). Data from multivariate conditional logistic regression model analysis showed that hopelessness, negative life-events and family history of suicide were relationship of attempted suicide in patients with major depression with OR values as 0.33 (95% CI: 0.22-0.99), 7.68 (95% CI: 5.79-13.74), 6.64 (95% CI: 2.48-11.04), 2.98 (95% CI: 1.17-5.04) respectively. There was no first level interaction between any of the two risk factors. CONCLUSION Results from the study supported the idea that hopelessness, negative life-events and family history of suicide were risk factors of attempted suicide in major deprbssion while TPH2 gene rs7305115 A/A might be the protective factor.

[A case-control study on the risk factors for attempted suicide in patients with major depression].

Background
Suicide and major depressive disorders (MDD) are strongly associated, and genetic factors are responsible for at least part of the variability in suicide risk. We investigated whether variation at the tryptophan hydroxylase-2 (TPH2) gene rs7305115 SNP may predispose to suicide attempts in MDD.

/pdf/effect-of-tryptophan-hydroxylase-2-rs7305115-snp-on-suicide-4fflq7am9p.pdf

Effect of tryptophan hydroxylase-2 rs7305115 SNP on suicide attempts risk in major depression.

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[A case-control study on the risk factors for attempted suicide in patients with major depression].

Effect of tryptophan hydroxylase-2 rs7305115 SNP on suicide attempts risk in major depression.