A Multivariate Genomic Investigation of the Externalizing Spectrum and Suicide Risk

Suicidal thoughts and behaviors originate from heterogeneous mechanisms, including behavioral disinhibition characteristic of "externalizing" disorders (e.g., substance use disorders, antisocial personality disorder, etc.). Prior work has demonstrated strong genetic overlap between externalizing and suicide attempts. In the current analysis, we investigate the co-occurrence between a broader array of suicide phenotypes (i.e., suicide deaths, non-fatal attempts, suicidal ideation) and the externalizing spectrum using data from the Million Veteran Program (MVP) Cohort. We leverage the large-scale MVP database to (1) estimate a latent genomic factor for externalizing comprised of MVP data (MVP-EXT) using genomic structural equation modeling (GenomicSEM), (2) validate these results against prior externalizing models and other traits, (3) examine the genetic overlap between externalizing and suicide outcomes using multiple approaches (e.g., genetic correlations, polygenic scores, and post mortem brain tissue of suicide deaths), and (4) explore whether phenotypic externalizing is prospectively associated with death by suicide. We identify 155 loci in our meta-analysis of European-like (EUR-like, N = 310,498) and African-like (AFR-like, N = 99,949) MVP participants. MVP-EXT showed a strong genetic correlation with a prior, non-MVP externalizing factor (rG = 0.87, 95% CI = 0.83, 0.91) and suicide attempt in both EUR-like (rG = 0.67, 95% CI = 0.60, 0.74) and AFR-like (rG = 0.62, 95% CI = 0.42, 0.81) veterans. MVP-EXT polygenic scores 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) in independent cohorts. MVP-EXT associated genes showed significant enrichment particularly within inhibitory neurons in suicide deaths compared to deaths from other causes. A phenotypic score for externalizing was prospectively associated with death by suicide in MVP (HR = 1.39, 95% CI = 1.33, 1.45). In total, our results reiterate that, while the relation between suicide with internalizing disorders has generally received more attention, externalizing is an important risk factor for suicide related behaviors. Greater attention should be paid to these problems as potential antecedents of suicide-related behaviors.