¹Yale University School of Medicine, Psychiatry, West Haven, CT, United States, ²VA Connecticut Healthcare Center, Psychiatry Research, West Haven, Connecticut, United States

Background: Cannabis use has gained legal and societal acceptance in many locations worldwide in recent years, with consequent increases in both cannabis lifetime use (CanLU) and cannabis use disorder (CanUD). Both CanLU and CanUD are genetically influenced, and knowledge of the specifics of how genes affect risk for these traits can help improve our understanding of their biology, and how they relate genetically to other traits. This talk will summarize our work on these traits.

Aims & Objectives: The availability of large biobank samples such as the Million Veteran Program and AllOfUs (in the US) and the UK Biobank (in the UK) has made it feasible to conduct powerful genetic studies of these traits. We completed multi-ancestral GWAS analyses of CanLU and CanUD and considered their relationships to a range of psychiatric, substance use, and medical traits, and to each other.

Method: We used genomewide association analysis, linkage disequilibrium score regression, genomic structural equation modeling (gSEM), and Mendelian randomization (MR).

Results: We identified multiple associated risk loci in European and African ancestry participants. Patterns of genetic correlation tended to differ between CanLU and CanUD, with the latter trait tending to be associated with deleterious traits to a greater extent than CanLU. MR results showed causal effects for CanUD and CanLU on opioid use disorder, problematic alcohol use, and smoking traits. Many of these relationships were bidirectional. gSEM supported that CanLU and CanUD load onto different genetic factors; CanUD clustered with other use disorders and CanLU, with impulsivity-related traits. CanUD, compared to CanLU, also showed more bidirectional causal effects with a range of psychiatric phenotypes.

Discussion & Conclusions: CanUD and CanLU have complex genetic architectures, with features in common with each other and with other substance use traits, as well as distinct features. Knowledge of this genetic architecture opens the possibility of drug repurposing in the interest of improving treatment. CanUD and cannabis use can increase the risk of developing other substance use disorders, psychiatric disorders, and medical disorders. These relationships will increase in importance and in terms of their consequences on public health as use and abuse of cannabis increase in many worldwide populations.