The Externalizing Spectrum and Suicide Risk: Insights from Genomics and Electronic Health Records in over 500,000 Veterans

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, suggesting this may provide valuable information about underlying suicide risk. MethodsWe investigated the co-occurrence between suicide-related outcomes and externalizing using data from the Million Veteran Program (MVP, N = 591,818) to: (1) create and validate a latent genomic factor for externalizing (MVP-EXT), (2) examine the genetic overlap between externalizing and suicidality using genetic correlations and polygenic scores (PGS), and (3) leverage the known genetic overlap to explore the prospective association between phenotypic externalizing and suicide death in electronic health records where measures of behavioral disinhibition are often lacking. ResultsThe genetic correlation between MVP-EXT and a prior externalizing factor that did not contain MVP data was strong (rG = 0.87, 95% CI = 0.83, 0.91). MVP-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) descent. PGSs 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). An externalizing score derived from recent diagnoses (past 12-month at baseline) was prospectively associated with suicide death (HR = 1.36, 95% CI = 1.30, 1.42). 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, reflective of impulsivity and behavioral disinhibition, is an important indicator of risk for suicide-related outcomes. The results here demonstrate externalizing and suicide may share a common genetic origin, in part, and this can be leveraged in electronic health records where measures of behavioral disinhibition are often non-existent. 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.