Genetics of cannabis ever-use and frequency across ancestries implicate novel loci and brain-specific biology

Cannabis use is widespread, with genetic differences partly explaining variation in individual patterns of use. We performed the largest-to-date genome-wide association study (GWAS) meta-analysis of cannabis ever-use (N=736,322, 76% European ancestry) and various measures of frequency of use (N=269,160 cannabis users, 84% European ancestry). We identified 54 independent genome-wide significant loci for ever-use and 6 for frequency and show that the genetic architecture of ever-use, frequency, and cannabis use disorder (CUD) are overlapping but distinguishable. We identified 63 loci that were associated with common liability ( All-cannabis) to different cannabis use traits in European-ancestry individuals. Across analyses, we identified 75 unique loci that had not previously been implicated in cannabis use. Gene prioritization analyses identified 349 genes for ever-use, 5 genes for frequency of use, and 429 for All-cannabis, including previously identified and novel genes. We found enrichment of genetic signals for cannabis use in biologically meaningful categories and relevant human brain cell types, including excitatory neuronal populations. There were substantial genetic correlations between cannabis use and a range of psychiatric disorders and substance use traits, while cannabis polygenic scores were associated with increased risk of psychiatric disorders. Mendelian Randomization showed evidence for (bidirectional) causal associations between cannabis use and ADHD, bipolar disorder, schizophrenia and PTSD.