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

doi:10.1016/S2215-0366(20)30339-4

Meta-Analysis

. 2020 Dec;7(12):1032-1045.

doi: 10.1016/S2215-0366(20)30339-4. Epub 2020 Oct 20.

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

Emma C Johnson¹, Ditte Demontis², Thorgeir E Thorgeirsson³, Raymond K Walters⁴, Renato Polimanti⁵, Alexander S Hatoum⁶, Sandra Sanchez-Roige⁷, Sarah E Paul⁸, Frank R Wendt⁵, Toni-Kim Clarke⁹, Dongbing Lai¹⁰, Gunnar W Reginsson³, Hang Zhou⁵, June He⁶, David A A Baranger¹¹, Daniel F Gudbjartsson¹², Robbee Wedow⁴, Daniel E Adkins¹³, Amy E Adkins¹³, Jeffry Alexander¹⁴, Silviu-Alin Bacanu¹⁴, Tim B Bigdeli¹⁵, Joseph Boden¹⁶, Sandra A Brown¹⁷, Kathleen K Bucholz⁶, Jonas Bybjerg-Grauholm¹⁸, Robin P Corley¹⁹, Louisa Degenhardt²⁰, Danielle M Dick²¹, Benjamin W Domingue²², Louis Fox⁶, Alison M Goate²³, Scott D Gordon²⁴, Laura M Hack²⁵, Dana B Hancock²⁶, Sarah M Hartz⁶, Ian B Hickie²⁷, David M Hougaard¹⁸, Kenneth Krauter²⁸, Penelope A Lind²⁴, Jeanette N McClintick²⁹, Matthew B McQueen³⁰, Jacquelyn L Meyers³¹, Grant W Montgomery³², Ole Mors³³, Preben B Mortensen³⁴, Merete Nordentoft³⁵, John F Pearson³⁶, Roseann E Peterson³⁷, Maureen D Reynolds³⁸, John P Rice⁶, Valgerdur Runarsdottir³⁹, Nancy L Saccone⁴⁰, Richard Sherva⁴¹, Judy L Silberg⁴², Ralph E Tarter³⁸, Thorarinn Tyrfingsson³⁹, Tamara L Wall⁴³, Bradley T Webb¹⁴, Thomas Werge⁴⁴, Leah Wetherill¹⁰, Margaret J Wright⁴⁵, Stephanie Zellers⁴⁶, Mark J Adams⁹, Laura J Bierut⁶, Jason D Boardman⁴⁷, William E Copeland⁴⁸, Lindsay A Farrer⁴¹, Tatiana M Foroud¹⁰, Nathan A Gillespie³⁷, Richard A Grucza⁶, Kathleen Mullan Harris⁴⁹, Andrew C Heath⁶, Victor Hesselbrock⁵⁰, John K Hewitt¹⁹, Christian J Hopfer⁵¹, John Horwood¹⁶, William G Iacono⁴⁶, Eric O Johnson²⁶, Kenneth S Kendler³⁷, Martin A Kennedy⁵², Henry R Kranzler⁵³, Pamela A F Madden⁶, Hermine H Maes⁴², Brion S Maher⁵⁴, Nicholas G Martin²⁴, Matthew McGue⁴⁶, Andrew M McIntosh⁹, Sarah E Medland²⁴, Elliot C Nelson⁶, Bernice Porjesz³¹, Brien P Riley¹⁴, Michael C Stallings¹⁹, Michael M Vanyukov³⁸, Scott Vrieze⁴⁶; Psychiatric Genomics Consortium Substance Use Disorders Workgroup; Lea K Davis⁵⁵, Ryan Bogdan⁸, Joel Gelernter⁵⁶, Howard J Edenberg⁵⁷, Kari Stefansson⁵⁸, Anders D Børglum², Arpana Agrawal⁶

Collaborators, Affiliations

Collaborators

Psychiatric Genomics Consortium Substance Use Disorders Workgroup:
Raymond Walters, Renato Polimanti, Emma Johnson, Jeanette McClintick, Alexander Hatoum, June He, Frank Wendt, Hang Zhou, Mark Adams, Amy Adkins, Fazil Aliev, Silviu-Alin Bacanu, Anthony Batzler, Sarah Bertelsen, Joanna Biernacka, Tim Bigdeli, Li-Shiun Chen, Toni-Kim Clarke, Yi-Ling Chou, Franziska Degenhardt, Anna Docherty, Alexis Edwards, Pierre Fontanillas, Jerome Foo, Louis Fox, 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, Dongbing Lai, 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, Sandra Sanchez-Roige, Melanie Schwandt, Richard Sherva, Fabian Streit, Jana Strohmaier, Nathaniel Thomas, Jen-Chyong Wang, Bradley Webb, Robbee Wedow, Leah Wetherill, Amanda Wills, Jason Boardman, Danfeng Chen, Doo-Sup Choi, William Copeland, Robert Culverhouse, Norbert Dahmen, Louisa Degenhardt, 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, Joseph Boden, 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, Kathleen Mullan Harris, Andrew Heath, Victor Hesselbrock, John Hewitt, Christian Hopfer, John Horwood, William Iacono, Eric Johnson, Jaakko Kaprio, Victor Karpyak, Kenneth Kendler, Henry Kranzler, Kenneth Krauter, 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, Bernice Porjesz, John Rice, Marcella Rietschel, Brien Riley, Richard Rose, Dan Rujescu, Pei-Hong Shen, Judy Silberg, Michael Stallings, Ralph Tarter, Michael Vanyukov, Scott Vrieze, Tamara Wall, John Whitfield, Hongyu Zhao, Benjamin Neale, Joel Gelernter, Howard Edenberg, Arpana Agrawal

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA. Electronic address: emma.c.johnson@wustl.edu.
² Department of Biomedicine-Human Genetics and Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark.
³ CNS Department, Reykjavik, Iceland.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
⁶ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
⁷ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, USA.
⁹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹ Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹² Statistics Department, Reykjavik, Iceland; School of Engineering and Natural Sciences, Iceland University, Reykjavik, Iceland.
¹³ Department of Psychiatry, University of Utah, Salt Lake City, UT, USA; Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
¹⁴ Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
¹⁶ Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
¹⁷ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Psychology and Office of Research Affairs, University of California San Diego, La Jolla, CA, USA.
¹⁸ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Department for Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark.
¹⁹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
²⁰ National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia.
²¹ Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
²² Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.
²³ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
²⁶ GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, Durham, NC, USA.
²⁷ Brain and Mind Centre, University of Sydney, Sydney, Australia.
²⁸ Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA; University of Colorado Boulder, Boulder, CO, USA.
²⁹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁰ Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
³¹ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA; Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
³² Institute for Molecular Bioscience, University of Queensland, QLD, Australia.
³³ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Psychosis Research Unit, Aarhus University Hospital, Aarhus, Denmark.
³⁴ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
³⁵ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
³⁶ Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand; Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
³⁷ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
³⁸ School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
³⁹ SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.
⁴⁰ Department of Genetics, Washington University School of Medicine, St Louis, MO, USA; Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
⁴¹ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
⁴² Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁴³ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁴⁴ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, and Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.
⁴⁵ Queensland Brain Institute, University of Queensland, QLD, Australia.
⁴⁶ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
⁴⁷ Institute of Behavioral Science and Department of Sociology, University of Colorado Boulder, Boulder, CO, USA.
⁴⁸ Department of Psychiatry, University of Vermont Medical Center, Burlington, VT, USA.
⁴⁹ Department of Sociology, and The Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁰ Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA.
⁵¹ Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA.
⁵² Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁵³ Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
⁵⁴ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵⁵ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Psychiatry and Behavioral Sciences, and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶ Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Genetics, and Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
⁵⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵⁸ deCODE Genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

PMID: 33096046
PMCID: PMC7674631
DOI: 10.1016/S2215-0366(20)30339-4

Meta-Analysis

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

Emma C Johnson et al. Lancet Psychiatry. 2020 Dec.

. 2020 Dec;7(12):1032-1045.

doi: 10.1016/S2215-0366(20)30339-4. Epub 2020 Oct 20.

Authors

Collaborators

Psychiatric Genomics Consortium Substance Use Disorders Workgroup:
Raymond Walters, Renato Polimanti, Emma Johnson, Jeanette McClintick, Alexander Hatoum, June He, Frank Wendt, Hang Zhou, Mark Adams, Amy Adkins, Fazil Aliev, Silviu-Alin Bacanu, Anthony Batzler, Sarah Bertelsen, Joanna Biernacka, Tim Bigdeli, Li-Shiun Chen, Toni-Kim Clarke, Yi-Ling Chou, Franziska Degenhardt, Anna Docherty, Alexis Edwards, Pierre Fontanillas, Jerome Foo, Louis Fox, 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, Dongbing Lai, 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, Sandra Sanchez-Roige, Melanie Schwandt, Richard Sherva, Fabian Streit, Jana Strohmaier, Nathaniel Thomas, Jen-Chyong Wang, Bradley Webb, Robbee Wedow, Leah Wetherill, Amanda Wills, Jason Boardman, Danfeng Chen, Doo-Sup Choi, William Copeland, Robert Culverhouse, Norbert Dahmen, Louisa Degenhardt, 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, Joseph Boden, 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, Kathleen Mullan Harris, Andrew Heath, Victor Hesselbrock, John Hewitt, Christian Hopfer, John Horwood, William Iacono, Eric Johnson, Jaakko Kaprio, Victor Karpyak, Kenneth Kendler, Henry Kranzler, Kenneth Krauter, 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, Bernice Porjesz, John Rice, Marcella Rietschel, Brien Riley, Richard Rose, Dan Rujescu, Pei-Hong Shen, Judy Silberg, Michael Stallings, Ralph Tarter, Michael Vanyukov, Scott Vrieze, Tamara Wall, John Whitfield, Hongyu Zhao, Benjamin Neale, Joel Gelernter, Howard Edenberg, Arpana Agrawal

Affiliations

¹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA. Electronic address: emma.c.johnson@wustl.edu.
² Department of Biomedicine-Human Genetics and Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark.
³ CNS Department, Reykjavik, Iceland.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
⁶ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
⁷ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, USA.
⁹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹⁰ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹ Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹² Statistics Department, Reykjavik, Iceland; School of Engineering and Natural Sciences, Iceland University, Reykjavik, Iceland.
¹³ Department of Psychiatry, University of Utah, Salt Lake City, UT, USA; Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
¹⁴ Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
¹⁶ Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
¹⁷ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Psychology and Office of Research Affairs, University of California San Diego, La Jolla, CA, USA.
¹⁸ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Department for Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark.
¹⁹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
²⁰ National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia.
²¹ Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
²² Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.
²³ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁴ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁵ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
²⁶ GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, Durham, NC, USA.
²⁷ Brain and Mind Centre, University of Sydney, Sydney, Australia.
²⁸ Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA; University of Colorado Boulder, Boulder, CO, USA.
²⁹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁰ Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
³¹ Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA; Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
³² Institute for Molecular Bioscience, University of Queensland, QLD, Australia.
³³ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Psychosis Research Unit, Aarhus University Hospital, Aarhus, Denmark.
³⁴ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
³⁵ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
³⁶ Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand; Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
³⁷ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
³⁸ School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
³⁹ SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.
⁴⁰ Department of Genetics, Washington University School of Medicine, St Louis, MO, USA; Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
⁴¹ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
⁴² Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁴³ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁴⁴ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, and Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.
⁴⁵ Queensland Brain Institute, University of Queensland, QLD, Australia.
⁴⁶ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
⁴⁷ Institute of Behavioral Science and Department of Sociology, University of Colorado Boulder, Boulder, CO, USA.
⁴⁸ Department of Psychiatry, University of Vermont Medical Center, Burlington, VT, USA.
⁴⁹ Department of Sociology, and The Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁰ Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA.
⁵¹ Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA.
⁵² Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁵³ Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
⁵⁴ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵⁵ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Psychiatry and Behavioral Sciences, and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶ Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Genetics, and Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA; Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
⁵⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵⁸ deCODE Genetics/Amgen, Reykjavik, Iceland; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

PMID: 33096046
PMCID: PMC7674631
DOI: 10.1016/S2215-0366(20)30339-4

Erratum in

Correction to Lancet Psychiatry 2020; 7: 1032-45.
[No authors listed] [No authors listed] Lancet Psychiatry. 2022 Apr;9(4):e12. doi: 10.1016/S2215-0366(22)00065-7. Epub 2022 Feb 24. Lancet Psychiatry. 2022. PMID: 35219447 Free PMC article. No abstract available.

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.

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Figures

**Figure 1**
Manhattan plot of the European ancestry-only genome-wide meta-analysis

**Figure 2**
Genetic correlations between CUD, cannabis use, and other traits of interest CUD=cannabis use disorder. GWAS=genome-wide association studies. rg=genetic correlation. *Significantly genetically correlated with CUD. †Significantly different correlations between CUD and cannabis use (α=0·002).

**Figure 3**
PheWAS associations between polygenic risk for CUD and phenotypes in the BioVU biobank The 46 phenotypes shown are significantly associated with CUD (p<3·74 × 10⁻⁵, corrected for 1335 phenotypes tested). CUD=cannabis use disorder. PheWAS=phenotype-wide association study. NOS=not otherwise specified. SIRS=systemic inflammatory response syndrome.

**Figure 4**
Polygenic risk score associations with white matter volume in drug-naive children Total white matter volume was regressed on polygenic risk scores for CUD and cannabis use (in separate models). CUD=cannabis use disorder.

See this image and copyright information in PMC

Comment in

Using genetic information to inform policy on cannabis.
Hines LA, Treur JL, Jones HJ, Sallis HM, Munafò MR. Hines LA, et al. Lancet Psychiatry. 2020 Dec;7(12):1002-1003. doi: 10.1016/S2215-0366(20)30377-1. Epub 2020 Oct 20. Lancet Psychiatry. 2020. PMID: 33096047 No abstract available.

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References

1. Verweij KJH, Zietsch BP, Lynskey MT. Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction. 2010;105:417–430. - PMC - PubMed
1. Agrawal A, Lynskey MT, Hinrichs A. A genome-wide association study of DSM-IV cannabis dependence. Addict Biol. 2011;16:514–518. - PMC - PubMed
1. Demontis D, Rajagopal VM, Thorgeirsson TE. Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nat Neurosci. 2019;22:1066–1074. - PMC - PubMed
1. Sherva R, Wang Q, Kranzler H. Genome-wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks. JAMA Psychiatry. 2016;73:472–480. - PMC - PubMed
1. Pasman JA, Verweij KJH, Gerring Z. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat Neurosci. 2018;21:1161–1170. - PMC - PubMed

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[1] Verweij KJH, Zietsch BP, Lynskey MT. Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction. 2010;105:417–430. - PMC - PubMed

[2] Verweij KJH, Zietsch BP, Lynskey MT. Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction. 2010;105:417–430. - PMC - PubMed

[3] Agrawal A, Lynskey MT, Hinrichs A. A genome-wide association study of DSM-IV cannabis dependence. Addict Biol. 2011;16:514–518. - PMC - PubMed

[4] Agrawal A, Lynskey MT, Hinrichs A. A genome-wide association study of DSM-IV cannabis dependence. Addict Biol. 2011;16:514–518. - PMC - PubMed

[5] Demontis D, Rajagopal VM, Thorgeirsson TE. Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nat Neurosci. 2019;22:1066–1074. - PMC - PubMed

[6] Demontis D, Rajagopal VM, Thorgeirsson TE. Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nat Neurosci. 2019;22:1066–1074. - PMC - PubMed

[7] Sherva R, Wang Q, Kranzler H. Genome-wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks. JAMA Psychiatry. 2016;73:472–480. - PMC - PubMed

[8] Sherva R, Wang Q, Kranzler H. Genome-wide association study of cannabis dependence severity, novel risk variants, and shared genetic risks. JAMA Psychiatry. 2016;73:472–480. - PMC - PubMed

[9] Pasman JA, Verweij KJH, Gerring Z. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat Neurosci. 2018;21:1161–1170. - PMC - PubMed

[10] Pasman JA, Verweij KJH, Gerring Z. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat Neurosci. 2018;21:1161–1170. - PMC - PubMed

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

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