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Transl Psychiatry. 2016 Mar 29;6:e769. doi: 10.1038/tp.2016.36.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Author information

1
Department of Complex Trait Genetics, VU Amsterdam, Center for Neurogenomics and Cognitive Research, Amsterdam, The Netherlands.
2
Department of Psychiatry, Academic Medical Centre, Amsterdam, The Netherlands.
3
Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
4
Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
5
Department of Developmental Psychology and EMGO Institute for Health and Care Research, VU University, Amsterdam, The Netherlands.
6
The Hospital for Sick Children Research Institute, Toronto, Canada.
7
Department of Psychology, University of Illinois Urbana-Champaign, Champaign, IL, USA.
8
Department of Human Neurogenetics, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
9
Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
10
Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
11
Estonian Genome Center, University of Tartu, Tartu, Estonia.
12
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
13
Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
14
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
15
Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
16
Twin Research and Genetic Epidemiology, King's College London, London, UK.
17
Biomedical Genetics Department, Boston University School of Medicine, Boston, MA, USA.
18
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
19
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
20
Department of Medicine, Harvard Medical School, Boston, MA, USA.
21
School of Social and Community Medicine, University of Bristol, Bristol, UK.
22
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
23
Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
24
Research Centre Adolescent Development, Utrecht University, Utrecht, The Netherlands.
25
Department of Psychology and Psychiatry, University of California San Diego, La Jolla, CA, USA.
26
The LifeLines Cohort Study, University of Groningen, Groningen, The Netherlands.
27
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
28
Genetic Epidemiology, Molecular Epidemiology and Neurogenetics Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
29
Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
30
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
31
Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.
32
Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA.
33
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
34
Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
35
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
36
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
37
Department of Psychology, University of Notre Dame, Notre Dame, IN, USA.
38
Developmental Psychology, Tilburg University, Tilburg, The Netherlands.
39
Interdisciplinary Center for Pathology and Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
40
Department of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
41
Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, IN, USA.
42
Department of Psychology and Neuroscience, Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
43
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
44
Rotman Research Institute, Baycrest, Toronto, ON, Canada.
45
Department of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada.
46
Center for the Developing Brain, Child Mind Institute, New York, NY, USA.
47
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
48
UK Centre for Tobacco and Alcohol Studies and School of Experimental Psychology, University of Bristol, Bristol, UK.
49
Department of Psychiatry, Genetics, and Neurobiology, Yale University School of Medicine and VA CT, West Haven, CT, USA.
50
Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands.

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.

PMID:
27023175
PMCID:
PMC4872459
DOI:
10.1038/tp.2016.36
[Indexed for MEDLINE]
Free PMC Article

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