Genetic Pathways Point to the Biology Underlying the Association Between Cannabis Use Disorder and Psychosis

Cannabis use is associated with increased risk of psychotic disorders, but the underlying biological mechanisms remain unclear. We used genetic data to investigate the molecular pathways contributing to the association between cannabis use disorder (CUD) and psychosis. We conducted a cross-disorder meta-analysis of genome-wide association studies (GWASs) on schizophrenia and bipolar I disorder ( N = 547,508) to define a combined-psychosis genetic liability. Using summary statistics from the latest cross-ancestry GWAS of CUD, we performed multitrait conditional analysis (psychosis conditioned on CUD), Mendelian randomization (MR), MR-clustering (MR-CLUST), and exploratory pathway-specific polygenic score (pPGS) analyses in the EU-GEI (European Network of National Schizophrenia Networks Studying Gene-Environment Interactions) first-episode psychosis case-control sample. We identified 553 independent genome-wide significant loci for psychosis, including 122 novel associations. More pathways were nominally associated with psychosis and CUD than expected by chance. MR analyses supported bidirectional causal effects (psychosis on CUD β IVW = 0.19, 95% CI, 0.15–0.22; CUD on psychosis β IVW = 0.31, 95% CI, 0.22–0.41). MR-CLUST identified 3 distinct clusters from CUD to psychosis, enriched for overlapping but functionally distinct pathways, including intracellular signaling, synaptic function, and neuronal development. In the EU-GEI sample, the glutamate pPGS consistently predicted psychosis status across the full sample and cannabis users and nonusers, explaining the most additional variance in each group. Our findings highlight shared and distinct molecular pathways linking CUD and psychosis. Glutamate signaling emerged as a key mechanism across analysis strategies, while MR-CLUST revealed heterogeneous causal routes from cannabis use to psychosis. These insights may inform risk prediction and targeted interventions for cannabis-related psychosis. Cannabis use disorder (CUD) is linked to a higher risk of psychosis, but the biological reasons for this are not well understood. We combined large genetic datasets to study how genes and molecular pathways connect CUD and psychosis. We found evidence that the relationship goes both ways: Genetic risk for psychosis increases the likelihood of CUD, and genetic risk for CUD increases the likelihood of psychosis. Specific biological pathways, especially those involved in glutamate signaling and brain development, appeared important. We also showed that these pathways help predict psychosis risk in people who use cannabis.