GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Abstract

Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.

Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.

Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10^-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10^-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.

Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Keywords: Biological Markers; Depressive Disorders; Genetics; Schizophrenia Spectrum and Other Psychotic Disorders; Self-Harm; Suicide.

FIGURE 1.. Manhattan plot of multi-ancestry GWAS meta-analysis of suicide attempt^a

^aThe x-axis shows genomic position and the y-axis shows statistical significance as −log₁₀(p). The horizontal line shows the genome-wide significance threshold (p<5.0×10⁻⁸). Labels represent the nearest gene to the index SNP. Regional plots of the eight genome-wide significant loci across ancestry admixture populations and the four genome-wide significant loci in subjects of European ancestry admixtures are presented in Figures S3–S14 in the online supplement.

FIGURE 2.. Forest plot of genetic correlations of the multi-ancestry GWAS meta-analyses of suicide attempt with physical and mental health phenotypes^a

^aThe x-axis presents genetic correlation values with 95% confidence intervals, and the y-axis presents the discovery GWAS for multiple phenotypes. ISGC = International Suicide Genetics Consortium meta-analysis; ISGC + MVP=the primary meta-analysis including GWASs from both ISGC and Million Veteran Program sets of cohorts; ISGC + MVP | MDD and PTSD=the combined GWAS meta-analysis of both cohorts conditioning on major depressive disorder and posttraumatic stress disorder.