A Multivariate Genomic Investigation of the Externalizing Spectrum and Suicide Risk

BackgroundSuicide-related outcomes, including suicidal ideation, suicide attempt, and suicide death, originate from heterogeneous mechanisms, including behavioral disinhibition characteristic of "externalizing" disorders (e.g., substance use disorders, ADHD, etc.). Prior work has demonstrated strong genetic overlap between externalizing and suicide attempts. MethodsWe investigated the co-occurrence between suicide-related outcomes and externalizing using data from the Million Veteran Program (MVP, N = 591,818) to: (1) estimate a latent genomic factor for externalizing (MVP-EXT), (2) examine the genetic overlap between externalizing and suicidality using genetic correlations, polygenic scores (PGS), and post mortem brain tissue, and (3) explore the prospective association between phenotypic externalizing and suicide death. ResultsMVP-EXT was genetically correlated with suicide attempt in veterans of European-like (rG = 0.67, 95% CI = 0.60, 0.74) and African-like (rG = 0.62, 95% CI = 0.42, 0.81) ancestries. PGS were associated with suicidal ideation (OR = 1.09, 95% CI = 1.05, 1.13) and suicide attempts (OR = 1.20, 95% CI = 1.13, 1.27). MVP-EXT associated genes were enriched within inhibitory neurons in a sample containing suicide deaths. Externalizing was prospectively associated with suicide death (HR = 1.39, 95% CI = 1.33, 1.45). The 5-year cumulative incidence for suicide death was [~]5x greater for those with 4+ past year externalizing codes compared to those with none. ConclusionsExternalizing is an important indicator of risk for suicide-related outcomes. While the relation between suicide with internalizing disorders has generally received more attention, greater attention should be paid to externalizing as potential antecedents of suicide-related outcomes.