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

Abstract

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.

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“…This is a clear example of the importance of including at least some genotyping in recruiting subjects and then interpreting the results of an intervention with THC; the genetic basis of cannabis use and the variable reactions to cannabinoid administration may be driven and “flavored” by polymorphisms of genes such as CNR1 , CADM2 , FOXP2 , CHRNA2 , ANKFN1 , INTS7 , PI4K2B , CSMD1 , CST7 , ACSS1 , OPRM1 , and SCN9A . In exploring the extent to which an individual may respond to a cannabinoid(s), a genuinely comprehensive trial would ideally include a genomic profile of the subjects; with today’s technology, this prospect appears to be realistic and cost-effective (Hillmer et al, 2021 [ 62 ]; Verweij et al, 2022 [ 63 ]).…”

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“…The presence of FOXP2 in the large introgression desert on chromosome 7 may have less to do with its well-known role in sensori-motor learning, and more to do with its associations with behavioral traits pertaining to sociability and externalizing behavior (Tielbeek et al, 2022 ; Verweij et al, 2022 ).…”