title: Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.
abstract: Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.
authors.affiliation: Department of Complex Trait Genetics, VU Amsterdam, Center for Neurogenomics and Cognitive Research, Amsterdam, The Netherlands.|Department of Psychiatry, Academic Medical Centre, Amsterdam, The Netherlands.
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authors.affiliation: Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
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authors.affiliation: Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, The Netherlands.|Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.|Department of Developmental Psychology and EMGO Institute for Health and Care Research, VU University, Amsterdam, The Netherlands.
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authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
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authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
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authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.|Genetic Epidemiology, Molecular Epidemiology and Neurogenetics Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019002:CD56 Antigen / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D002189:Marijuana Abuse / Q000235:genetics*; D008385:Marijuana Smoking / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015221:Potassium Channels / Q000235:genetics; D000081033:Potassium Channels, Sodium-Activated; D055815:Young Adult
chemical_list: C556123:CADM2 protein, human; D019002:CD56 Antigen; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C480494:KCNT2 protein, human; D008565:Membrane Proteins; C522918:NCAM1 protein, human; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; C430910:SCOC protein, human