Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits

Cannabis use disorder (CanUD) has increased with the legalization of the use of cannabis. Around 20% of individuals using cannabis develop CanUD, and the number of users has grown with increasing ease of access. CanUD and other substance use disorders (SUDs) are associated phenotypically and genetically. We leveraged new CanUD genomics data to undertake genetically-informed analyses with unprecedented power, to investigate the genetic architecture and causal relationships between CanUD and lifetime cannabis use with risk for developing SUDs and substance use traits. Analyses included calculating local and global genetic correlations, genomic structural equation modeling (genomicSEM), and Mendelian Randomization (MR). Results from the genetic correlation and genomicSEM analyses demonstrated that CanUD and cannabis use differ in their relationships with SUDs and substance use traits. We found significant causal effects of CanUD influencing all the analyzed traits: opioid use disorder (OUD) (Inverse variant weighted, IVW beta = 0.925 +/- 0.082), problematic alcohol use (PAU) (IVW beta = 0.443 +/- 0.030), drinks per week (DPW) (IVW beta = 0.182 +/- 0.025), Fagerstrom Test for Nicotine Dependence (FTND) (IVW beta = 0.183 +/- 0.052), cigarettes per day (IVW beta = 0.150 +/- 0.045), current versus former smokers (IVW beta = 0.178 +/- 0.052), and smoking initiation (IVW beta = 0.405 +/- 0.042). We also found evidence of bidirectionality showing that OUD, PAU, smoking initiation, smoking cessation, and DPW all increase risk of developing CanUD. For cannabis use, bidirectional relationships were inferred with PAU, smoking initiation, and DPW; cannabis use was also associated with a higher risk of developing OUD (IVW beta = 0.785 +/- 0.266). GenomicSEM confirmed that CanUD and cannabis use load onto different genetic factors. We conclude that CanUD and cannabis use can increase the risk of developing other SUDs. This has substantial public health implications; the move towards legalization of cannabis use may be expected to increase other kinds of problematic substance use. These harmful outcomes are in addition to the medical harms associated directly with CanUD.