Investigating the Polygenic Relationship Between Cannabis Use and Schizophrenia in the All of Us Research Program

ObjectiveDecades of research have identified a strong association between heavy cannabis use and schizophrenia, with evidence of correlated genetic factors. However, many studies on the genetic relationship between cannabis use and psychosis have lacked data on both phenotypes within the same individuals, creating challenges due to unmeasured confounding. We aimed to address this by using multi-modal data from the All of Us Research Program, which contains genetic data as well as information on schizophrenia diagnosis and cannabis use. MethodsWe tested the association between cannabis use disorder (CUD) and schizophrenia polygenic scores (PGS) and schizophrenia and heavy cannabis use. We tested models where both CUD and schizophrenia PGS were included as joint predictors of heavy cannabis use and schizophrenia case status. We defined three sets of cases based on comorbidities: relaxed (assessing for only the primary condition), strict (excluding for both conditions), and dual-comorbidity (including both conditions). ResultsCUD and schizophrenia polygenic liability were independently associated with heavy cannabis use; the schizophrenia PGS effect was very modest. In contrast, both schizophrenia and CUD PGS were independently associated with schizophrenia, with independent significant effects of CUD PGS. Polygenic liability to CUD was associated with schizophrenia in individuals without a documented history of cannabis use, suggesting widespread pleiotropy. ConclusionsThese findings underscore the need for comprehensive models that integrate genetic risk factors for heavy cannabis use to advance our understanding of schizophrenia aetiology.