Genetic Propensities for Psychiatric Disorders Reveal Distinct Pathways Linking Substance Use and Suicidality

This study investigates how genetic propensity for psychiatric disorders contributes to suicidal ideation or attempts via cannabis or opioid use—the two most commonly used federally controlled substances in the U.S. Using data from over 32,000 participants in the All of Us Research Program, we computed polygenic risk scores (PRS) for ten psychiatric conditions. Logistic regression and mediation analyses were used to examine both direct and indirect effects on suicidal behaviors, with substance use as a mediator. To explore bi-directional effects, we also used “reversed” mediation models to evaluate whether suicidality, regarded as psychological distress associated with hopelessness/impulsivity, could mediate polygenic risk–substance use associations with substance use disorders. Cannabis and opioid use significantly mediated the associations between genetic risk for attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) and suicidality. Specifically, the largest mediation fraction was observed for ADHD (60%), suggesting that individuals with high genetic liability for ADHD using cannabis or opioids are more likely to increase suicide risk than others. In reversed mediation models, suicidality mediated associations between genetic risk and substance use, most notably for anxiety disorders (43% mediated via opioid use), indicating that genetic risk for anxiety may lead to psychological distress marked by hopelessness or impulsivity, which in turn increases the likelihood of substance misuse. These findings highlight bidirectional mechanisms underlying the relationship between genetic propensities for psychiatric disorders, substance us disorders, and suicide, implying complementary targets for suicide prevention and early intervention strategies.