The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond

Cannabis is among the most widely consumed psychoactive substances worldwide. Individual differences in cannabis use phenotypes can partly be explained by genetic differences. Technical and methodological advances have increased our understanding of the genetic aetiology of cannabis use. This narrative review discusses the genetic literature on cannabis use, covering twin, linkage, and candidate-gene studies, and the more recent genome-wide association studies (GWASs), as well as the interplay between genetic and environmental factors. Not only do we focus on the insights that these methods have provided on the genetic aetiology of cannabis use, but also on how they have helped to clarify the relationship between cannabis use and co-occurring traits, such as the use of other substances and mental health disorders. Twin studies have shown that cannabis use is moderately heritable, with higher heritability estimates for more severe phases of use. Linkage and candidate-gene studies have been largely unsuccessful, while GWASs so far only explain a small portion of the heritability. Dozens of genetic variants predictive of cannabis use have been identified, located in genes such as CADM2, FOXP2, and CHRNA2. Studies that applied multivariate methods (twin models, genetic correlation analysis, polygenic score analysis, genomic structural equation modelling, Mendelian randomisation) indicate that there is considerable genetic overlap between cannabis use and other traits (especially other substances and externalising disorders) and some evidence for causal relationships (most convincingly for schizophrenia). We end our review by discussing implications of these findings and suggestions for future work.