Genome-wide association study meta-analysis of suicide attempt identifies twelve genome-wide significant loci and implicates genetic risks for specific health factors

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Abstract Objective Suicidal behavior is heritable and a major cause of death worldwide. Two large-scale genome-wide association studies (GWAS) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The current 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 was comprised of 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 eQTL 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<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 was observed. There was shared genetic variation of SA with ADHD, smoking, and risk tolerance after conditioning SA on both major depressive disorder and post-traumatic 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 major ancestry admixtures, in veteran and civilian populations, and in attempt versus death.

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