Objective Decades 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. Methods We 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). Results CUD 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. Conclusions These findings underscore the need for comprehensive models that integrate genetic risk factors for heavy cannabis use to advance our understanding of schizophrenia aetiology.

The authors have declared no competing interest.

This work was supported by the National Institute on Drug Abuse (NIDA DP1DA054394 JJM, SSR; NIDA K01DA051759 ECJ), and the California Tobacco-Related Disease Research Program (T32IR5226). JYK is supported by a Canada Research Chair in Translational Neuropsychopharmacology. AA receives funding from R01DA054869 and R21DA061592. MDF and IAZ were supported by MRC SRF (MRC MR/T007818/1).

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