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

Abstract

Suicidal behaviors (SBs), 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 SB is supported by family, twin, and adoption studies. The aim of this paper is to review recent genetic association studies in SBs 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 (BDNFs)] are linked to SBs, 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 single-nucleotide polymorphisms in numerous genes. We have included 104 such studies, of which 10 are family-based association studies and 11 are GWAS. Numerous meta-analyses of case–control studies have shown significant associations of SB with variants in the serotonin transporter gene (5-HTT or SLC6A4) and the tryptophan hydroxylase 1 gene (TPH1), but others report contradictory results. The gene encoding BDNF and its receptor (NTRK2) are also promising candidates. Only two of the GWAS 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.

Genomewide association studies of suicide attempts in US soldiers

“…Prior genetic association studies of suicidality have relied on clinical or other targeted samples, primarily patients with mood disorders [Galfalvy et al 2015; Perlis et al 2010; Schosser et al 2011; Willour et al 2012], or patients taking antidepressant medication [Menke et al 2012; Perroud et al 2012]. Since suicide attempts occur at substantial rates outside of clinically identified samples, examining non-clinical, population-based samples is important to fully understand genetic and other risk factors for SA, which may differ depending on sample characteristics [Mirkovic et al 2016]. We focused on soldiers in the US Army, where better understanding and prevention of suicidality has been a major concern [Engel 2013; LeardMann et al 2013; Nock et al 2014; Ursano et al 2015].…”

“…Several genomewide association studies (GWAS) of suicidality have been reported [Mirkovic et al 2016], mostly limited to analyses of suicide attempts among patients with mood disorders. In four large GWAS comparing mood disorder patients (bipolar and/or major depressive disorder) with and without a history of suicide attempts, no genomewide significant (GWS) loci were detected [Galfalvy et al 2015; Perlis et al 2010; Schosser et al 2011; Willour et al 2012].…”

Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior

“…In addition, carriers of the long allele with concomitant higher levels of testosterone showed lower cortisol secretion after threat indicating neuropsychiatric resilience for this combination in humans (62). A recent review on genetic association studies of suicidal behavior identified 5HTTLPR and BDNF among few others as most promising candidates (63). Male-specific endocrine factors may play a key role in this association.…”

Genomewide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide

“…Compared to the estimated number of ~19,000 genes in the human genome, 13 there are a relatively small number of genes in the literature specifically associated with suicide: about 100 genes from candidate gene, expression, and epigenetic studies, and approximately another 100 from GWAS studies 4 (200/19000=~1%). From our overlapping regions, 7/101=6.93% have prior suicide associations, significantly greater than the expected rate (Z=5.69, p<0.0001).…”

“…2,3 Discovery of specific genetic risk variants could result in better insight into biological mechanisms of risk. Recent growth in the number of suicide genetic studies has resulted in promising genetic findings from candidate gene and genome-wide association studies, 4 though not surprisingly given the high degree of predicted genetic heterogeneity for suicide risks, replicated findings have been rare. Replication is also hampered by sample differences across studies, including differences in demographics, primary diagnoses, or outcomes, which range from suicidal ideation and behaviors to completed suicide; evidence suggests these etiologies may be distinct.…”