Authors

Abstract

The age- and sex-adjusted suicide rate has steadily increased over the past two decades in theUnited States, particularly among military veterans. Unfortunately, the biologicalunderpinnings of suicide remain largely unknown. In order to identify pan-ethnic and ancestryspecific loci associated with risk for attempting suicide among veterans, we conducted agenome-wide association study (GWAS) of suicide attempts within a large, multi-ethnic cohortof U.S. veterans enrolled in the Million Veterans Program (MVP). A case-control GWAS studywas conducted in the MVP cohort comparing veterans with a documented history of suicideattempts in the electronic health record (EHR; N=14,089) to veterans with no documentedhistory of suicidal thoughts or behaviors in the EHR (N=395,064). GWAS was performedseparately in each ancestry group, controlling for sex, age and genetic substructure. Metaanalysis was used to identify pan-ethnic risk loci. Lifetime history of suicide attempts wasdefined from EHR data, including International Classification of Diseases codes, suicidebehavior reports, and mental health survey responses. Two pan-ethnic genome-wide significantloci from chromosomes 20 (p=3.64x10-9) and 1 (p=3.69x10-8) were associated with increased riskfor suicide attempts. Both loci demonstrated homogeneity of direction and magnitude of effects across ancestral groups. The chromosome 20 locus was also genome-wide significant within theAfrican-American subset (p=1.38x10-8). Notably, a strong pan-ethnic signal at the DopamineReceptor D2 locus (p=1.77x10-7) was also identified and subsequently replicated in a large,independent international cohort (p=7.97x10-4). Additionally, ancestry-specific genome-widesignificant loci were also detected in chromosome 8 among African-Americans (p=2.90x10-8),chromosome 3 among European-Americans (p=3.20x10-8), Fibrillin 1 among Asian-Americans (ps<2.90x10-8), and in three loci among Hispanic-Americans (chromosome 3; p=1.76x10-8;chromosome 6; p=2.08x10-8; chromosome 13; p=3.17x10-8). Pathway analyses suggestedoverrepresentation of many biological pathways with clinical significance, including oxytocinsignaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, andcircadian rhythm. Taken together, these findings confirm that the genetic architectureunderlying suicide attempt risk is complex and includes both pan-ethnic and ancestry-specificrisk loci. Moreover, pathway analyses suggested many commonly impacted biologicalpathways that could inform development of improved therapeutics for suicide prevention.