AbstractIn 2015, ~800,000 people died by suicide worldwide. For every death by suicide there are as many as 25 suicide attempts, which can result in serious injury even when not fatal. Despite this large impact on morbidity and mortality, the genetic influences on suicide attempt are poorly understood. We performed a genome-wide association study (GWAS) of severity of suicide attempts to investigate genetic influences. A discovery GWAS was performed in Yale-Penn sample cohorts of European Americans (EAs, n = 2,439) and African Americans (AAs, n = 3,881). We found one genome-wide significant (GWS) signal in EAs near the gene LDHB (rs1677091, p = 1.07 × 10⁻⁸) and three GWS associations in AAs: ARNTL2 on chromosome 12 (rs683813, p = 2.07 × 10⁻⁸), FAH on chromosome 15 (rs72740082, p = 2.36 × 10⁻⁸), and on chromosome 18 (rs11876255, p = 4.61 × 10⁻⁸) in the Yale-Penn discovery sample. We conducted a limited replication analysis in the completely independent Army-STARRS cohorts. rs1677091 replicated in Latinos (LAT, p = 6.52 × 10⁻³). A variant in LD with FAH rs72740082 (rs72740088; r² = 0.68) was replicated in AAs (STARRS AA p = 5.23 × 10⁻³; AA meta, 1.51 × 10⁻⁹). When combined for a trans-population meta-analysis, the final sample size included n = 20,153 individuals. Finally, we found significant genetic overlap with major depressive disorder (MDD) using polygenic risk scores from a large GWAS (r² = 0.007, p = 6.42 × 10⁻⁵). To our knowledge, this is the first GWAS of suicide attempt severity. We identified GWS associations near genes involved in anaerobic energy production (LDHB), circadian clock regulation (ARNTL2), and catabolism of tyrosine (FAH). These findings provide evidence of genetic risk factors for suicide attempt severity, providing new information regarding the molecular mechanisms involved.