1. A large-scale genome-wide association study meta-analysis of cannabis use disorder
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Emma C Johnson, Ditte Demontis, Thorgeir E Thorgeirsson, Raymond K Walters, Renato Polimanti, Alexander S Hatoum, Sandra Sanchez-Roige, Sarah E Paul, Frank R Wendt, Toni-Kim Clarke, Dongbing Lai, Gunnar W Reginsson, Hang Zhou, June He, David A A Baranger, Daniel F Gudbjartsson, Robbee Wedow, Daniel E Adkins, Amy E Adkins, Jeffry Alexander, Silviu-Alin Bacanu, Tim B Bigdeli, Joseph Boden, Sandra A Brown, Kathleen K Bucholz, Jonas Bybjerg-Grauholm, Robin P Corley, Louisa Degenhardt, Danielle M Dick, Benjamin W Domingue, Louis Fox, Alison M Goate, Scott D Gordon, Laura M Hack, Dana B Hancock, Sarah M Hartz, Ian B Hickie, David M Hougaard, Kenneth Krauter, Penelope A Lind, Jeanette N McClintick, Matthew B McQueen, Jacquelyn L Meyers, Grant W Montgomery, Ole Mors, Preben B Mortensen, Merete Nordentoft, John F Pearson, Roseann E Peterson, Maureen D Reynolds, John P Rice, Valgerdur Runarsdottir, Nancy L Saccone, Richard Sherva, Judy L Silberg, Ralph E Tarter, Thorarinn Tyrfingsson, Tamara L Wall, Bradley T Webb, Thomas Werge, Leah Wetherill, Margaret J Wright, Stephanie Zellers, Mark J Adams, Laura J Bierut, Jason D Boardman, William E Copeland, Lindsay A Farrer, Tatiana M Foroud, Nathan A Gillespie, Richard A Grucza, Kathleen Mullan Harris, Andrew C Heath, Victor Hesselbrock, John K Hewitt, Christian J Hopfer, John Horwood, William G Iacono, Eric O Johnson, Kenneth S Kendler, Martin A Kennedy, Henry R Kranzler, Pamela A F Madden, Hermine H Maes, Brion S Maher, Nicholas G Martin, Matthew McGue, Andrew M McIntosh, Sarah E Medland, Elliot C Nelson, Bernice Porjesz, Brien P Riley, Michael C Stallings, Michael M Vanyukov, Scott Vrieze, Lea K Davis, Ryan Bogdan, Joel Gelernter, Howard J Edenberg, Kari Stefansson, Anders D Børglum, Arpana Agrawal, Raymond Walters, Emma Johnson, Jeanette McClintick, Alexander Hatoum, Frank Wendt, Mark Adams, Amy Adkins, Fazil Aliev, Anthony Batzler, Sarah Bertelsen, Joanna Biernacka, Tim Bigdeli, Li-Shiun Chen, Yi-Ling Chou, Franziska Degenhardt, Anna Docherty, Alexis Edwards, Pierre Fontanillas, Jerome Foo, Josef Frank, Ina Giegling, Scott Gordon, Laura Hack, Annette Hartmann, Sarah Hartz, Stefanie Heilmann-Heimbach, Stefan Herms, Colin Hodgkinson, Per Hoffman, Jouke Hottenga, Martin Kennedy, Mervi Alanne-Kinnunen, Bettina Konte, Jari Lahti, Marius Lahti-Pulkkinen, Lannie Ligthart, Anu Loukola, Brion Maher, Hamdi Mbarek, Andrew McIntosh, Matthew McQueen, Jacquelyn Meyers, Yuri Milaneschi, Teemu Palviainen, John Pearson, Roseann Peterson, Samuli Ripatti, Euijung Ryu, Nancy Saccone, Jessica Salvatore, Melanie Schwandt, Fabian Streit, Jana Strohmaier, Nathaniel Thomas, Jen-Chyong Wang, Bradley Webb, Amanda Wills, Jason Boardman, Danfeng Chen, Doo-Sup Choi, William Copeland, Robert Culverhouse, Norbert Dahmen, Benjamin Domingue, Sarah Elson, Mark Frye, Wolfgang Gäbel, Caroline Hayward, Marcus Ising, Margaret Keyes, Falk Kiefer, John Kramer, Samuel Kuperman, Susanne Lucae, Michael Lynskey, Wolfgang Maier, Karl Mann, Satu Männistö, Bertram Müller-Myhsok, Alison Murray, John Nurnberger, Aarno Palotie, Ulrich Preuss, Katri Räikkönen, Maureen Reynolds, Monika Ridinger, Norbert Scherbaum, Marc Schuckit, Michael Soyka, Jens Treutlein, Stephanie Witt, Norbert Wodarz, Peter Zill, Daniel Adkins, Dorret Boomsma, Laura Bierut, Sandra Brown, Kathleen Bucholz, Sven Cichon, E. Jane Costello, Harriet de Wit, Nancy Diazgranados, Danielle Dick, Johan Eriksson, Lindsay Farrer, Tatiana Foroud, Nathan Gillespie, Alison Goate, David Goldman, Richard Grucza, Dana Hancock, Andrew Heath, John Hewitt, Christian Hopfer, William Iacono, Eric Johnson, Jaakko Kaprio, Victor Karpyak, Kenneth Kendler, Henry Kranzler, Paul Lichtenstein, Penelope Lind, Matt McGue, James MacKillop, Pamela Madden, Hermine Maes, Patrik Magnusson, Nicholas Martin, Sarah Medland, Grant Montgomery, Elliot Nelson, Markus Nöthen, Abraham Palmer, Nancy Pederson, Brenda Penninx, John Rice, Marcella Rietschel, Brien Riley, Richard Rose, Dan Rujescu, Pei-Hong Shen, Judy Silberg, Michael Stallings, Ralph Tarter, Michael Vanyukov, Tamara Wall, John Whitfield, Hongyu Zhao, Benjamin Neale, Howard Edenberg, Technology Centre, Department of Psychology and Logopedics, Developmental Psychology Research Group, University Management, HUSLAB, Genetic Epidemiology, Institute for Molecular Medicine Finland, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Faculty of Arts, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Research Programs Unit, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, Johan Eriksson / Principal Investigator, Clinicum, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, and APH - Methodology
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Risk ,Marijuana Abuse ,medicine.medical_specialty ,Alcohol abuse ,Disease ,Polymorphism, Single Nucleotide ,3124 Neurology and psychiatry ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,Borderline personality disorder ,Biological Psychiatry ,business.industry ,Articles ,Mental illness ,medicine.disease ,Mental health ,030227 psychiatry ,3. Good health ,Substance abuse ,Psychiatry and Mental health ,Translational science ,business ,Genome-Wide Association Study ,Psychopathology - Abstract
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 (r g 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.
- Published
- 2020
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