Genomewide association studies of suicide attempts in US soldiers

Abstract

Suicide is a global public health problem with particular resonance for the U.S. military. Genetic risk factors for suicidality are of interest as indicators of susceptibility and potential targets for intervention. We utilized population-based nonclinical cohorts of US military personnel (discovery: N = 473 cases and N = 9778 control subjects; replication: N = 135 cases and N = 6879 control subjects) and a clinical case-control sample of recent suicide attempters (N = 51 cases and N = 112 control subjects) to conduct GWAS of suicide attempts (SA). Genomewide association was evaluated within each ancestral group (European-, African-, Latino-American) and study using logistic regression models. Meta-analysis of the European ancestry discovery samples revealed a genomewide significant locus in association with SA near MRAP2 (melanocortin 2 receptor accessory protein 2) and CEP162 (centrosomal protein 162); 12 genomewide significant SNPs in the region; peak SNP rs12524136-T, OR=2.88, p=5.24E-10. These findings were not replicated in the European ancestry subsamples of the replication or suicide attempters samples. However, the association of the peak SNP remained significant in a meta-analysis of all studies and ancestral subgroups (OR = 2.18, 95%CI 1.70, 2.80). Polygenic risk score (PRS) analyses showed some association of SA with bipolar disorder. The association with SNPs encompassing MRAP2, a gene expressed in brain and adrenal cortex and involved in neural control of energy homeostasis, points to this locus as a plausible susceptibility gene for suicidality that should be further studied. Larger sample sizes will be needed to confirm and extend these findings.

Significant shared heritability underlies suicide attempt and clinically predicted probability of attempting suicide

“…Epidemiological and family studies imply a substantial genetic component with estimates of the heritability of suicide attempt as high as 55% [6][7][8][9] . However, largescale genetic studies remain difficult due to challenges in phenotypic ascertainment and collecting large enough samples to have the power to identify replicable genetic associations or to directly estimate the proportion of heritability contributed from common genetic variation [10][11][12][13] . Thus, despite both the major public health impact and the strong evidence of heritability, the genetic architecture of suicide and suicidal behaviors remains poorly understood 14 .…”

Genome-wide association study of suicide attempt in psychiatric disorders identifies association with major depression polygenic risk scores

“…These studies have failed to identify any replicable genetic associations, likely due to limited sample sizes that were underpowered to detect the genetic effects typical for a single SNP. Other GWAS have examined subjects recruited specifically on the basis of suicide attempt, or suicide attempters and non-attempters from population-based cohorts, but to date no loci have been robustly implicated (11)(12)(13).…”

Identification of gene ontology and pathways implicated in suicide behavior: Systematic review and enrichment analysis of GWAS studies

“…Initially, the literature search provided 191 articles (PubMed = 97, Scopus = 93) associated to GWAS and suicide. After the methodological inclusion/exclusion criteria, we obtain 21 eligible studies (Table ; Bani‐Fatemi et al, ; Coon et al, ; Erlangsen et al, ; Galfalvy et al, , ; Gross et al, ; Kimbrel et al, ; Laje et al, ; Levey et al, ; Menke et al, ; Mullins et al, ; Perlis et al, ; Perroud et al, ; Pulay & Rethelyi, ; Schosser et al, ; Sokolowski et al, , ; Stein et al, ; Strawbridge et al, ; Willour et al, ; Zai et al, ). Regarding the clinical situation of the individuals included, the behaviors that were mainly studied were SA and SI with frequent psychiatric diagnostics of major depressive disorder or bipolar disorder.…”