Pathways from Polygenic Risk to Suicidality: Effects of Alcohol Use Disorder and Childhood Adversity

Abstract Background The prevalences of suicidal ideation (SI) and suicide attempt (SA) are influenced by genetic, behavioral, and environmental factors. Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may mediate or moderate genetic liability for suicidality. Methods Using data from 10,275 participants (43.8% female; 47.2% African-like genetic ancestry [AFR], 52.8% European-like genetic ancestry [EUR]), we tested whether polygenic scores (PGS) for SI and SA predicted lifetime SI or SA. We also evaluated whether alcohol use disorder (AUD) mediated these associations and whether adverse childhood experiences (ACEs) moderated the direct and indirect pathways. Results Although there were significant direct associations of the SA PGS with SA (AFR: b = 0.36, SE = 0.01; EUR: b = 0.17, SE = 0.01; both p s < 2e-16), the SI PGS did not predict SI (p > 0.55). AUD mediated SA genetic risk (average causal mediation effect (ACME): AFR = 0.01, 95% CI [0.01-0.01]; EUR = 0.02, 95% CI [0.01-0.02]; both p s < 2e-16). Moderation analyses indicated that indirect effects were attenuated by ACEs score (ΔACME: AFR = 0.02, p < 2e-16; EUR = 0.01, p = 0.03). There was neither mediation nor moderated mediation for SI. Conclusions Genetic liability to SA operates partly through AUD, particularly among individuals with lower childhood adversity. Under higher adversity, alternative pathways to SA likely predominate. These findings highlight the need to consider distinct etiological pathways to the development of suicidality and the relevance of AUD as a modifiable target for suicide prevention among individuals at high genetic liability.