Polygenic prediction of cannabis-related outcomes over time: Evidence from the ALSPAC longitudinal cohort and the EU-GEI case-control study

Polygenic risk scores (PRSs) for cannabis use disorder (CUD), major depressive disorder (MDD), insomnia, and chronic pain might contribute to patterns of cannabis use, including problematic cannabis use. We examined PRSs for the above traits and different patterns of cannabis use across developmental stages using the ALSPAC longitudinal cohort (N = 8,224 participants with genotype data) and the EU-GEI case-control study (N = 994 [56.9%] controls and 752 [43.1%] first-episode psychosis cases with genotype data) for replication. We fitted regression models to test associations between PRSs and patterns of cannabis use at different ages. An interaction term was included to test whether the association between early cannabis initiation and heavy use is moderated by PRSs. Genetic liability to CUD, MDD, and pain was consistently associated with heavier use of cannabis. In the ALSPAC sample, linear regression models showed that CUD PRS was associated with CAST score at 20, and 24 years. MDD and pain PRSs were associated with CAST scores at 17, 20, and 24 years. In the EU-GEI, CUD PRS and pain PRS were associated with “weekly-to-daily” use of cannabis. Similarly, in the cases-only sample, CUD PRS and pain PRS were associated with weekly-to-daily use. In the controls-only sample, only CUD PRS was associated with weekly-to-daily use. This reflects an underlying vulnerability that may lead some people to use cannabis more heavily as a coping mechanism. However, age at initiation (ALSPAC = 7.1%, EU-GEI = 4.53%) explained a greater proportion of the variance of problematic cannabis use than polygenic liability, indicating atime-sensitiveintervention target.