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Nat Neurosci. 2018 Sep;21(9):1161-1170. doi: 10.1038/s41593-018-0206-1. Epub 2018 Aug 27.

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.

Author information

1
Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands.
2
Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands.
3
Genetic Epidemiology, Statistical Genetics, and Translational Neurogenomics Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
4
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
5
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
6
MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
7
Department of Biological Psychology/Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
8
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
9
23andMe, Inc., Mountain View, CA, USA.
10
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
11
Vanderbilt Genetics Institute; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
12
Peter Boris Centre for Addictions Research and Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University/St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
13
Department of Psychology, University of Illinois Urbana-Champaign, Champaign, IL, USA.
14
Department of Youth and Family, Utrecht University, Utrecht, the Netherlands.
15
Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
16
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
17
Department of Developmental Psychology and EMGO Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
18
Estonian Genome Center, University of Tartu, Tartu, Estonia.
19
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
20
Hospital for Sick Children, Toronto, Ontario, Canada.
21
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
22
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
23
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain.
24
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
25
Rotman Research Institute, Baycrest, Toronto, Ontario, Canada.
26
Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
27
Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland.
28
Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
29
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
30
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
31
Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
32
UK Centre for Tobacco and Alcohol Studies and School of Experimental Psychology, University of Bristol, Bristol, UK.
33
Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
34
Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands. j.vink@bsi.ru.nl.

Abstract

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.

PMID:
30150663
DOI:
10.1038/s41593-018-0206-1

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