GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability
Disease areas:
clinical signs and symptoms
drug and alcohol-related diseases
mental health
Last updated:
Author(s):
Joëlle A. Pasman, Karin J. H. Verweij, Zachary Gerring, Sven Stringer, Sandra Sanchez-Roige, Jorien L. Treur, Abdel Abdellaoui, Michel G. Nivard, Bart M. L. Baselmans, Jue-Sheng Ong, Hill F. Ip, Matthijs D. van der Zee, Meike Bartels, Felix R. Day, Pierre Fontanillas, Sarah L. Elson, the 23andMe Research Team, Harriet de Wit, Lea K. Davis, James MacKillop, The Substance Use Disorders Working Group of the Psychiatric Genomics Consortium, International Cannabis Consortium, Jaime L. Derringer, Susan J. T. Branje, Catharina A. Hartman, Andrew C. Heath, Pol A. C. van Lier, Pamela A. F. Madden, Reedik Mägi, Wim Meeus, Grant W. Montgomery, A. J. Oldehinkel, Zdenka Pausova, Josep A. Ramos-Quiroga, Tomas Paus, Marta Ribases, Jaakko Kaprio, Marco P. M. Boks, Jordana T. Bell, Tim D. Spector, Joel Gelernter, Dorret I. Boomsma, Nicholas G. Martin, Stuart MacGregor, John R. B. Perry, Abraham A. Palmer, Danielle Posthuma, Marcus R. Munafò, Nathan A. Gillespie, Eske M. Derks, Jacqueline M. Vink
Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. 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. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.
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The main goal of our study is to quantify and understand the role of genetic variants, the environment (including lifestyle), and their interaction on outcomes…
