UC San Diego

Cannabis is one of the most widely used drugs globally. We performed genome-wide association studies (GWASs) of lifetime (N = 131,895) and frequency (N = 73,374) of cannabis use. For lifetime cannabis use, we identified two loci, one near CADM2 (rs35827242, p = 4.63E-12) and another near GRM3 (rs12673181, p = 6.90E-09). For frequency of cannabis use, we identified one locus near CADM2 (rs4856591, p = 8.10E-09; r2 = 0.76 with rs35827242). Lifetime and frequency of cannabis use were heritable (12.88 vs. 6.63%) and genetically correlated with previous GWASs of lifetime use and cannabis use disorder (CUD), as well as other substance use and cognitive traits. Polygenic scores (PGSs) for lifetime and frequency of cannabis use predicted cannabis use phenotypes in All of Us participants. A phenome-wide association study using a PGS for lifetime cannabis use to interrogate a hospital cohort replicated prior associations with substance use and mood disorders, and uncovered novel associations with celiac and infectious diseases. This work demonstrates the utility of pre-addiction phenotypes in cannabis use genomic discovery.