Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

Abstract

Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2, has previously been associated with substance use and risk-taking phenotypes [2-4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.