the ALDH2 and ADH1B loci19. Similarly to alcohol-related studies, PRS derived from smoking traits showed associations across traits related to multiple substances (e.g., cocaine, amphetamine, hallucinogens, ecstasy, and cannabis initiation, as well as DSM-5 AUD)87,90,91. For cannabis, PRS derived from use (versus dependence) phenotypes showed association with depression, self-harm behaviours, and cannabis use assessed in an independent cohort92. In addition to testing SUD PRS prediction other traits, some studies have investigated how PRS derived from other psychiatric traits predict (are associated with) SUD phenotypes. For example, cocaine dependence was significantly associated with multiple PRS related to schizophrenia, ADHD, major depressive disorder, children’s aggressive behaviour, and antisocial behaviour48. With respect to dual diagnoses93, schizophrenia PRS was associated with having any SUD diagnosis94 and, in an independent study, the same PRS was associated with lifetime tobacco smoking in women but not in men, with significant interactions of the PRS with sex and birth decade95. Several investigations have been conducted to understand the interplay between SUD genetic risk and environmental factors. In a recent review article about this topic96, the most reported frameworks were differential susceptibility and diathesis-stress, with substantial heterogeneity across environmental exposures, genetic factors, and outcomes tested.
