Department of Economics and Business Economics

A large-scale genome-wide association study meta-analysis of cannabis use disorder

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  • Emma C Johnson, The George Washington University School of Medicine, Washington, DC, USA.
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  • Ditte Demontis
  • Thorgeir E Thorgeirsson, Univ Iceland, University of Iceland, South Iceland Res Ctr
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  • Raymond K Walters, Broad Institute of Harvard and MIT
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  • Renato Polimanti, Yale School of Medicine, Yale University
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  • Alexander S Hatoum, The George Washington University School of Medicine, Washington, DC, USA.
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  • Sandra Sanchez-Roige, Department of Dermatology, University of California, San Diego, California; Department of Pediatrics, University of California, San Diego, California; Rady Children's Hospital, San Diego, California.
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  • Sarah E Paul, Washington Univ, Saint Louis University, Washington University (WUSTL), Dept Pediat, St Louis Sch Med
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  • Frank R Wendt, Yale School of Medicine, Yale University
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  • Toni-Kim Clarke, Edinburgh University, Edinburgh
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  • Dongbing Lai, Indiana University School of Medicine, South Bend, Indiana
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  • Gunnar W Reginsson, Univ Iceland, University of Iceland, South Iceland Res Ctr
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  • Hang Zhou, Yale School of Medicine, Yale University
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  • June He, The George Washington University School of Medicine, Washington, DC, USA.
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  • David A A Baranger, Section of Palliative Care and Medical Ethics, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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  • Daniel F Gudbjartsson, Univ Iceland, Landspitali National University Hospital, University of Iceland, Natl Univ Hosp Iceland
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  • Robbee Wedow, Broad Institute of Harvard and MIT
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  • Daniel E Adkins, Department of Chemistry, University of Utah, Utah.
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  • Amy E Adkins, Department of Chemistry, University of Utah, Utah.
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  • Jeffry Alexander, Virginia Commonwealth University Alcohol Research Center
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  • Silviu-Alin Bacanu, Virginia Commonwealth University Alcohol Research Center
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  • Tim B Bigdeli, SUNY Downstate Health Sciences University
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  • Joseph Boden, Univ Otago, University of Otago, Dept Zool
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  • Sandra A Brown, Department of Dermatology, University of California, San Diego, California; Department of Pediatrics, University of California, San Diego, California; Rady Children's Hospital, San Diego, California.
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  • Kathleen K Bucholz, The George Washington University School of Medicine, Washington, DC, USA.
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  • Jonas Bybjerg-Grauholm, Center for Neonatal Screening
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  • Robin P Corley, Univ Boulder Colorado, University of Colorado Boulder, University of Colorado System, Inst Arct & Alpine Res INSTAAR
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  • Louisa Degenhardt, Kirby Institute, University of New South Wales Medicine, University of New South Wales
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  • Danielle M Dick, Virginia Commonwealth Univ, Virginia Commonwealth University, Dept Psychiat
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  • Benjamin W Domingue, Stanford University Graduate School of Education
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  • Louis Fox, The George Washington University School of Medicine, Washington, DC, USA.
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  • Alison M Goate, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of
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  • Scott D Gordon, QIMR Berghofer Medical Research Institute
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  • Laura M Hack, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Dana B Hancock, Irish Center for Fetal and Neonatal Translational Research (INFANT).
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  • Sarah M Hartz, The George Washington University School of Medicine, Washington, DC, USA.
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  • Ian B Hickie, Sydney Medical School - Central, University of Sydney, Edward Ford Building A27, The University of Sydney, NSW 2006, Sydney, AUSTRALIA.
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  • David M Hougaard, Center for Neonatal Screening
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  • Kenneth Krauter, Univ Boulder Colorado, University of Colorado Boulder, University of Colorado System, Inst Arct & Alpine Res INSTAAR
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  • Penelope A Lind, QIMR Berghofer Medical Research Institute
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  • Jeanette N McClintick, Indiana University School of Medicine, South Bend, Indiana
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  • Matthew B McQueen, Univ Boulder Colorado, University of Colorado Boulder, University of Colorado System, Inst Arct & Alpine Res INSTAAR
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  • Jacquelyn L Meyers, SUNY Downstate Health Sciences University
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  • Grant W Montgomery, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
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  • Ole Mors
  • Preben B Mortensen
  • Merete Nordentoft, 1Copenhagen University Hospital, Copenhagen, Denmark. 2Aarhus University Hospital, Aarhus, Denmark. 3University of Copenhagen, Copenhagen, Denmark. 4Odense University Hospital, Odense, Denmark.
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  • John F Pearson, Univ Otago, University of Otago, Dept Zool
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  • Roseann E Peterson, Virginia Commonwealth Univ, Virginia Commonwealth University, Dept Psychiat
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  • Anders D Børglum
  • Psychiatric Genomics Consortium Substance Use Disorders Workgroup

BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

FINDINGS: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

INTERPRETATION: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

FUNDING: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

Original languageEnglish
JournalThe Lancet Psychiatry
Volume7
Issue12
Pages (from-to)1032-1045
Number of pages14
ISSN2215-0366
DOIs
Publication statusPublished - Dec 2020

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