NEW YORK (GenomeWeb) – The largest ever genome-wide association study of lifetime cannabis use has identified several genomic regions related to the risk of taking the drug. The loci overlap with the genetics of other substance use and mental health traits, such as smoking, alcohol use, and risk-taking behavior, and the study revealed a causal influence of schizophrenia risk on cannabis use.
Researchers from the International Cannabis Consortium (ICC), in collaboration with a research team from 23andMe, examined genomic data from nearly 185,000 people in a study published in Nature Neuroscience yesterday. Combined, they examined data from 35,297 individuals in ICC cohorts, 22,683 23andMe customers, and 126,785 subjects from the UK Biobank, identifying eight SNPs from six regions that were significant. Taken together, all measured genetic variants explained 11 percent of the variance, and the most promising candidates for future functional studies were CADM2, NCAM1, and multiple genes located at 16p11.2.
Cannabis use is a heritable trait, with one meta-analysis of twin studies previously estimating the heritability at 45 percent. A previous GWAS of around 32,000 individuals performed by ICC members and published in Translational Psychiatry implicated four genes in lifetime cannabis use — NCAM1, CADM2, SCOC, and KCNT2 — although none of the SNPs reached genome-wide significance in that study.
In the Nature Neuroscience study, led by senior author Jacqueline Vink of Radboud University in Nijmegen, the Netherlands, the gene-based tests revealed 35 significant genes in 16 regions, while S-PrediXcan analyses found 21 genes had different expression levels for cannabis users compared to nonusers. Across all analyses, the strongest finding was for CADM2, which the researchers wrote has been associated with substance use and risk-taking behavior, and which "may play a role in a broader personality profile of sensation-seeking and risk-taking behavior in general."
Significant genetic correlations were found with 14 of 25 tested substance use and mental health–related traits, including smoking, alcohol use, schizophrenia, and risk-taking. Genetic correlation analyses yielded positive associations between cannabis use and traits such as substance use and mental health phenotypes, with the researchers noting "substantial genetic correlations with risk-taking behavior and openness to experience," and, unexpectedly, educational attainment.
Mendelian randomization analysis also showed evidence for a causal positive influence of schizophrenia risk on cannabis use.
The relationship between cannabis use and schizophrenia has been the subject of intensive research and debate, the authors noted, but the direction of causation has not been firmly established.
The researchers used a method to perform Mendelian randomization on summary statistics from other GWAS studies — a technique recently used to home in on loci linked to intelligence and neuroticism — and found weak evidence for a causal link between cannabis use and schizophrenia but much stronger evidence for a causal link between schizophrenia and cannabis use, suggesting individuals with schizophrenia have a higher risk to start using cannabis.
Previously, a 2016 study in JAMA found three significant SNP associations for cannabis use, but in the Nature Neuroscience study, two of these sites were not available in the data — although the authors noted they were located in genes that were not significant in gene-based results — while one was not significant. The authors also cited a study published as a preprint in BioRxiv that found one independent significant signal on chromosome 8 to be associated with cannabis dependence, while neither the SNP nor the gene were associated with lifetime cannabis use in their own study.
However, both previous studies focused on cannabis dependence, and the authors argued that one gene those studies found is not associated with the initial stage of cannabis use, which they said is more linked to personality and risk taking than to cannabis' effects on the brain.
Limitations of the study included the fact that it combined experimentational users and frequent or regular users into a single group, with substantial variability in age as well as in the prevalence and policies regarding cannabis use in the subjects' different countries, the authors said.
Furthermore, they noted that the Mendelian randomization analysis was based on five SNPs, and the summary statistics of some of the traits used for the genetic correlation were based on a small sample size, so the power of these analyses may have been limited.