Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

Pasman, J. A.; Verweij, K. J. H.; Gerring, Z.; Stringer, S.; Sanchez-Roige, S.; Treur, J. L.; Abdellaoui, A.; Nivard, M. G.; Baselmans, B. M. L.; Ong, J.-S.; Ip, H. F.; van der Zee, M. D.; Bartels, M.; Day, F. R.; Fontanillas, P.; Elson, S. L.; the 23andMe Research Team,; de Wit, H.; Davis, L. K.; MacKillop, J.; International Cannabis Consortium,; Derringer, J. L.; Branje, S. J. T.; Hartman, C. A.; Heath, A. C.; van Lier, P. A. C.; Madden, P. A. F.; Magi, R.; Meeus, W.; Montgomery, G. W.; Oldehinkel, A. J.; Pausova, Z.; Ramos-Quiroga, J. A.; Paus, T.; Ribases, M.; Kaprio, J.; Boks, M. P. M

doi:10.1101/234294

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bioRxiv · 10.1101/234294

Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

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Abstract

Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2, has previously been associated with substance use and risk-taking phenotypes [2-4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.

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Pasman, J. A., Verweij, K. J. H., Gerring, Z., Stringer, S., Sanchez-Roige, S., Treur, J. L., Abdellaoui, A., Nivard, M. G., Baselmans, B. M. L., Ong, J.-S., Ip, H. F., van der Zee, M. D., Bartels, M., Day, F. R., Fontanillas, P., Elson, S. L., the 23andMe Research Team,, de Wit, H., Davis, L. K., MacKillop, J., International Cannabis Consortium,, Derringer, J. L., Branje, S. J. T., Hartman, C. A., Heath, A. C., van Lier, P. A. C., Madden, P. A. F., Magi, R., Meeus, W., Montgomery, G. W., Oldehinkel, A. J., Pausova, Z., Ramos-Quiroga, J. A., Paus, T., Ribases, M., Kaprio, J., Boks, M. P. M. 2018-01-08. Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use. https://doi.org/10.1101/234294

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