Abstract
Suicidal ideation, behaviors, and attempts are realized via heterogeneous mechanisms including behavioral disinhibition characteristic of “externalizing” disorders (e.g., substance use disorders, antisocial personality disorder, etc.). Previous analyses demonstrated that a latent externalizing (EXT) factor derived from genome-wide associations studies (GWAS) of substance use disorders, risky sexual behaviors, and ADHD was genetically correlated with lifetime suicide attempt (rG = 0.68). EXT polygenic scores (PGS) have also been associated with suicide attempt and ideation in the broader Million Veteran Program (MVP) sample, as well as within a cohort of veterans diagnosed with schizophrenia or bipolar disorder.
Here, we investigate the co-occurrence between suicidal phenotypes (completed attempts, prior behaviors, ideation, and self-harm) and EXT using genomic structural equation modeling (GenomicSEM) in MVP. We leverage genetic relationships between suicidality and psychiatric diagnoses (e.g. ADHD, alcohol, tobacco, and other substance use disorders), personality indices (e.g. extroversion and conscientiousness), and substance-use behaviors (e.g. lifetime smoking, frequency of binge drinking) to increase our power to detect specific genetic associations and improve the specificity of risk factors associated with suicidality. We ran all GWAS using SAIGE in veterans of primarily European ancestries, with effective sample sizes ranging from ∼40K to ∼365K, and then modeled a common EXT factor using GenomicSEM.
Preliminary results reveal a robust latent EXT factor in MVP (Chi-squared = 205.92, df = 17, p = 1.85 × 10-34; AIC = 243.91; CFI = 0.98; SRMR = 0.08). This MVP derived EXT factor correlates highly with an EXT factor, which did not include GWAS from MVP (rG = 0.89). Importantly, using only MVP GWAS, the MVP externalizing factor shows a strong genetic correlation with suicide attempt (rG = 0.70) and suicidal ideation (rG = 0.56).
Externalizing risk appears to have important implications for lifetime suicide risk. Next steps will (1) evaluate the biological, functional, and phenotypic pathways through which this EXT risk may manifest and contribute to overall risk for suicidality, and (2) extend the models to veterans of primarily admixed African and American ancestries.