<p>Cannabis is one of the most commonly used drugs in the world, and use is trending alarmingly higher. We aimed to examine the genetic basis of cannabis lifetime use (CanLU) and its genetic relationships with a variety of psychiatric- and physical health-related phenotypes. We conducted a multi-ancestral genome-wide association study (GWAS) of CanLU using data from All of Us in five genetic populations. We meta-analyzed the results of EUR participants with previously published CanLU data (total effective sample size: 258,823), and conducted a set of post-GWAS analyses, including genetic correlation analysis using LDSC, local genetic correlation analysis with LAVA, Mendelian randomization (MR) to assess causality, and phenomewide association analysis. We found 11 independent variants significantly associated with CanLU, most prominently <i>CADM2</i>*rs7609594 (<i>p</i> = 7.4 × 10⁻²⁰). CanLU was genetically correlated with traits related to openness to experience and risk taking, including substance use and sexual behaviors. MR demonstrated that most of these traits had a bidirectional causal relationship with CanLU, and six were locally genetically correlated with CanLU in a region that maps to <i>CADM2</i>. Genetic correlations sometimes differed from those previously observed for cannabis use disorder. Our results highlight the distinct genetic architecture of CanLU, and support the genetic, and biological, differentiation between CanLU and cannabis use disorder. Genetic correlations between CanLU and other risk taking- and substance use-related traits indicate a broad mutual genetic mechanism underlying these traits, and suggest involvement of <i>CADM2</i>. These findings provide potential targets for future prevention and intervention strategies for substance use and risk-taking behaviors.</p><p></p>