There are several strengths of this study. We demonstrated polygenic effects of common genetic variation on cannabis use, with weaker associations observed with persistence into DSM-CUD symptoms, in a well-characterized sample enriched for substance use problems. This provides molecular polygenic support for some genetic distinction of cannabis use and CUD demonstrated in several twin studies3. In addition, we used a relatively novel approach by testing GxE using polygenic scores, which allowed a focus on how polygenic influences on cannabis involvement differ as a function of psychosocial context. Further, we responded to critiques of GxE studies, which largely do not account for potential confounding of GxE effects25,26. Specifically, modeling of cross-term interactions revealed important influences of ancestry and sex on the PRS × frequency of religious service attendance effects observed in the current study. It should be noted that, while this study utilized genetic data to assign ancestry, which in our analytic sample was highly correlated with self-reported “race/ethnicity” (r: 0.95, p < 0.001), these are distinct constructs both shown to influence risk of substance use-related health outcomes, namely, through interactions
