mediated by the actual expression of the disorder among SAGE participants (e.g., people with higher MDD PRS in SAGE develop MDD, which in turn is associated with substance use disorders). Though data on ADHD diagnosis in SAGE were unavailable, repeating MDD PRS analyses while controlling for DSM-IV MDD diagnosis did not alter results, indicating that associations between PRS and substance use outcomes were not directly related to disorder expression (Supplementary Table S8). Longitudinal studies of well-characterized populations, as well as an increased emphasis on the study of substance use disorders in consortia such as the PGC, will be critical to further address these questions of temporality and comorbidity.
