Abstract Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study for lifetime cannabis use to date (N=184,765), we identified 8 genome-wide significant independent single nucleotide polymorphisms in 6 regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus non-users. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health traits, including smoking, alcohol use, schizophrenia, and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study gives new insights about the etiology of cannabis use and its relation with mental health.