. 2018 Dec;21(12):1656-1669.

doi: 10.1038/s41593-018-0275-1. Epub 2018 Nov 26.

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Raymond K Walters^{1

2}, Renato Polimanti³, Emma C Johnson⁴, Jeanette N McClintick⁵, Mark J Adams⁶, Amy E Adkins⁷, Fazil Aliev⁸, Silviu-Alin Bacanu⁹, Anthony Batzler¹⁰, Sarah Bertelsen¹¹, Joanna M Biernacka¹², Tim B Bigdeli¹³, Li-Shiun Chen⁴, Toni-Kim Clarke⁶, Yi-Ling Chou⁴, Franziska Degenhardt¹⁴, Anna R Docherty¹⁵, Alexis C Edwards¹⁶, Pierre Fontanillas¹⁷, Jerome C Foo¹⁸, Louis Fox⁴, Josef Frank¹⁸, Ina Giegling¹⁹, Scott Gordon²⁰, Laura M Hack²¹, Annette M Hartmann¹⁹, Sarah M Hartz⁴, Stefanie Heilmann-Heimbach¹⁴, Stefan Herms^{14

22}, Colin Hodgkinson²³, Per Hoffmann^{14

22}, Jouke Jan Hottenga²⁴, Martin A Kennedy²⁵, Mervi Alanne-Kinnunen²⁶, Bettina Konte¹⁹, Jari Lahti^{27

28}, Marius Lahti-Pulkkinen²⁸, Dongbing Lai²⁹, Lannie Ligthart²⁴, Anu Loukola²⁶, Brion S Maher³⁰, Hamdi Mbarek²⁴, Andrew M McIntosh³¹, Matthew B McQueen³², Jacquelyn L Meyers³³, Yuri Milaneschi³⁴, Teemu Palviainen²⁶, John F Pearson³⁵, Roseann E Peterson¹⁶, Samuli Ripatti^{1

2

26

36}, Euijung Ryu³⁷, Nancy L Saccone³⁸, Jessica E Salvatore^{8

16}, Sandra Sanchez-Roige³⁹, Melanie Schwandt⁴⁰, Richard Sherva⁴¹, Fabian Streit¹⁸, Jana Strohmaier¹⁸, Nathaniel Thomas⁷, Jen-Chyong Wang¹¹, Bradley T Webb⁹, Robbee Wedow^{1

2

42

43}, Leah Wetherill²⁹, Amanda G Wills⁴⁴; 23andMe Research Team; Jason D Boardman⁴⁵, Danfeng Chen², Doo-Sup Choi⁴⁶, William E Copeland⁴⁷, Robert C Culverhouse⁴⁸, Norbert Dahmen⁴⁹, Louisa Degenhardt⁵⁰, Benjamin W Domingue⁵¹, Sarah L Elson¹⁷, Mark A Frye⁵², Wolfgang Gäbel⁵³, Caroline Hayward⁵⁴, Marcus Ising⁵⁵, Margaret Keyes⁵⁶, Falk Kiefer⁵⁷, John Kramer⁵⁸, Samuel Kuperman⁵⁸, Susanne Lucae⁵⁵, Michael T Lynskey⁵⁹, Wolfgang Maier⁶⁰, Karl Mann⁵⁷, Satu Männistö⁶¹, Bertram Müller-Myhsok⁶², Alison D Murray⁶³, John I Nurnberger^{29

64}, Aarno Palotie^{1

2

26

65}, Ulrich Preuss^{19

66}, Katri Räikkönen²⁸, Maureen D Reynolds⁶⁷, Monika Ridinger⁶⁸, Norbert Scherbaum⁶⁹, Marc A Schuckit³⁹, Michael Soyka^{70

71}, Jens Treutlein¹⁸, Stephanie Witt¹⁸, Norbert Wodarz⁷², Peter Zill⁷¹, Daniel E Adkins^{15

73}, Joseph M Boden²⁵, Dorret I Boomsma²⁴, Laura J Bierut⁴, Sandra A Brown^{39

74}, Kathleen K Bucholz⁴, Sven Cichon²², E Jane Costello⁴⁷, Harriet de Wit⁷⁵, Nancy Diazgranados⁷⁵, Danielle M Dick^{7

76}, Johan G Eriksson⁷⁷, Lindsay A Farrer^{41

78}, Tatiana M Foroud²⁹, Nathan A Gillespie¹⁶, Alison M Goate¹¹, David Goldman^{23

40}, Richard A Grucza⁴, Dana B Hancock⁷⁹, Kathleen Mullan Harris⁸⁰, Andrew C Heath⁴, Victor Hesselbrock⁸¹, John K Hewitt⁸², Christian J Hopfer⁸³, John Horwood²⁵, William Iacono⁵⁶, Eric O Johnson⁸⁴, Jaakko A Kaprio^{26

36}, Victor M Karpyak⁵², Kenneth S Kendler⁹, Henry R Kranzler⁸⁵, Kenneth Krauter⁸⁶, Paul Lichtenstein⁸⁷, Penelope A Lind²⁰, Matt McGue⁵⁶, James MacKillop⁸⁸, Pamela A F Madden⁴, Hermine H Maes⁸⁹, Patrik Magnusson⁸⁷, Nicholas G Martin²⁰, Sarah E Medland²⁰, Grant W Montgomery⁹⁰, Elliot C Nelson⁴, Markus M Nöthen⁹¹, Abraham A Palmer^{39

92}, Nancy L Pedersen⁸⁷, Brenda W J H Penninx³⁴, Bernice Porjesz³³, John P Rice⁴, Marcella Rietschel¹⁸, Brien P Riley⁹, Richard Rose⁹³, Dan Rujescu¹⁹, Pei-Hong Shen²³, Judy Silberg¹⁶, Michael C Stallings⁸², Ralph E Tarter⁶⁷, Michael M Vanyukov⁶⁷, Scott Vrieze⁵⁶, Tamara L Wall³⁹, John B Whitfield²⁰, Hongyu Zhao⁹⁴, Benjamin M Neale^{1

2}, Joel Gelernter⁹⁵, Howard J Edenberg^{96

97}, Arpana Agrawal⁹⁸

Collaborators, Affiliations

Affiliations

¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Psychiatry, Yale School of Medicine and Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁴ Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA.
⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ University of Edinburgh, Division of Psychiatry, Edinburgh, UK.
⁷ Department of Psychology & College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
⁸ Virginia Commonwealth University, Department of Psychology, Richmond, VA, USA.
⁹ Virginia Commonwealth University Alcohol Research Center; Virginia Institute for Psychiatric and Behavioral Genetics; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
¹⁰ Mayo Clinic, Psychiatric Genomics and Pharmacogenomics Program, Rochester, MN, USA.
¹¹ Icahn School of Medicine at Mount Sinai, Department of Neuroscience, New York, NY, USA.
¹² Mayo Clinic, Department of Health Sciences Research, and Department of Psychiatry and Psychology, Rochester, MN, USA.
¹³ Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
¹⁴ Institute of Human Genetics, University of Bonn; and Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
¹⁵ University of Utah, Department of Psychiatry, Salt Lake City, UT, USA.
¹⁶ Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Richmond, VA, USA.
¹⁷ 23andMe, Inc, Mountain View, CA, USA.
¹⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁹ Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Psychotherapy and Psychosomatics, Halle, Germany.
²⁰ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²¹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
²² Human Genomics Research Group, Department of Biomedicine, University of Basel Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²³ NIH/NIAAA, Laboratory of Neurogenetics, Bethesda, MD, USA.
²⁴ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁵ University of Otago, Christchurch, New Zealand.
²⁶ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
²⁷ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
²⁸ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
²⁹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁰ Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
³¹ University of Edinburgh, Division of Psychiatry, Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
³² Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
³³ Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
³⁴ Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center/GGz inGeest, Amsterdam, The Netherlands.
³⁵ Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand.
³⁶ Department of Public Health, University of Helsinki, Helsinki, Finland.
³⁷ Mayo Clinic, Department of Health Sciences Research, Rochester, MN, USA.
³⁸ Washington University School of Medicine, Department of Genetics, St. Louis, MO, USA.
³⁹ University of California San Diego, Department of Psychiatry, San Diego, CA, USA.
⁴⁰ NIH/NIAAA, Office of the Clinical Director, Bethesda, MD, USA.
⁴¹ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
⁴² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴³ Department of Sociology, Harvard University, Cambridge, MA, USA.
⁴⁴ University of Colorado School of Medicine, Department of Pharmacology, Aurora, CO, USA.
⁴⁵ Institute of Behavioral Science and Department of Sociology, University of Colorado, Boulder, CO, USA.
⁴⁶ Mayo Clinic, Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, MN, USA.
⁴⁷ Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Durham, NC, USA.
⁴⁸ Washington University School of Medicine, Department of Medicine and Division of Biostatistics, St. Louis, MO, USA.
⁴⁹ Department of Psychiatry, University of Mainz, Mainz, Germany.
⁵⁰ National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
⁵¹ Stanford University Graduate School of Education, Stanford, CA, USA.
⁵² Mayo Clinic, Department of Psychiatry and Psychology, Rochester, MN, USA.
⁵³ Department of Psychiatry and Psychotherapy, University of Düsseldorf, Düsseldorf, Germany.
⁵⁴ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁵⁵ Max-Planck-Institute of Psychiatry, Munich, Germany.
⁵⁶ University of Minnesota, Department of Psychology, Minneapolis, MN, USA.
⁵⁷ Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁵⁸ University of Iowa Roy J and Lucille A Carver College of Medicine, Department of Psychiatry, Iowa City, IA, USA.
⁵⁹ Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁶⁰ Department of Psychiatry, University of Bonn, Bonn, Germany.
⁶¹ Institute for Health and Welfare, Helsinki, Finland.
⁶² Department of Statistical Genetics, Max-Planck-Institute of Psychiatry, Munich, Germany.
⁶³ The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK.
⁶⁴ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶⁵ Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁶⁶ Vitos Hospital Herborn, Department of Psychiatry and Psychotherapy, Herborn, Germany.
⁶⁷ University of Pittsburgh, School of Pharmacy, Pittsburgh, PA, USA.
⁶⁸ Department of Psychiatry and Psychotherapy, University of Regensburg Psychiatric Health Care Aargau, Regensburg, Germany.
⁶⁹ LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Department of Addictive Behaviour and Addiction Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany.
⁷⁰ Medical Park Chiemseeblick in Bernau-Felden, Chiemsee, Germany.
⁷¹ Psychiatric Hospital, Ludwig-Maximilians-University, Munich, Germany.
⁷² Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
⁷³ University of Utah, Department of Sociology, Salt Lake City, UT, USA.
⁷⁴ University of California, San Diego School of Medicine, Department of Psychology, San Diego, CA, USA.
⁷⁵ NIAAA Intramural Research Program, Bethesda, MD, USA.
⁷⁶ Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁷⁷ Department of General Practice and Primary Health Care, University of Helsinki, and National Institute for Health and Welfare, Helsinki, Finland.
⁷⁸ Departments of Neurology, Ophthalmology, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
⁷⁹ Center for Omics Discovery and Epidemiology, Behavioral Health Research Division, RTI International, Research Triangle Park, NC, USA.
⁸⁰ Department of Sociology and Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸¹ University of Connecticut School of Medicine, Department of Psychiatry, Farmington, CT, USA.
⁸² University of Colorado Boulder, Institute for Behavioral Genetics, Boulder, CO, USA.
⁸³ University of Colorado Denver, School of Medicine, Denver, CO, USA.
⁸⁴ RTI International, Fellows Program, Research Triangle Park, NC, USA.
⁸⁵ University of Pennsylvania Perelman School of Medicine, Center for Studies of Addiction, Department of Psychiatry and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
⁸⁶ University of Colorado Boulder, Department of Molecular, Cellular, and Developmental Biology, Boulder, CO, USA.
⁸⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, Sweden.
⁸⁸ Peter Boris Centre for Addictions Research, McMaster University/St. Joseph's Healthcare Hamilton; Michael G. DeGroote Centre for Medicinal Cannabis Research, Hamilton, Ontario, Canada.
⁸⁹ Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
⁹⁰ The Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁹¹ Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany.
⁹² University of California San Diego, Institute for Genomic Medicine, San Diego, CA, USA.
⁹³ Department of Psychological & Brain Sciences, Indiana University Bloomington, Bloomington, IN, USA.
⁹⁴ Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA.
⁹⁵ Departments of Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine, Veterans Affairs Connecticut Healthcare System, New Haven, CT, USA. joel.gelernter@yale.edu.
⁹⁶ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. edenberg@iu.edu.
⁹⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. edenberg@iu.edu.
⁹⁸ Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA. Arpana@wustl.edu.

PMID: 30482948
PMCID: PMC6430207
DOI: 10.1038/s41593-018-0275-1

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Raymond K Walters et al. Nat Neurosci. 2018 Dec.

. 2018 Dec;21(12):1656-1669.

doi: 10.1038/s41593-018-0275-1. Epub 2018 Nov 26.

Authors

Affiliations

¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Psychiatry, Yale School of Medicine and Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁴ Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA.
⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ University of Edinburgh, Division of Psychiatry, Edinburgh, UK.
⁷ Department of Psychology & College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA.
⁸ Virginia Commonwealth University, Department of Psychology, Richmond, VA, USA.
⁹ Virginia Commonwealth University Alcohol Research Center; Virginia Institute for Psychiatric and Behavioral Genetics; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
¹⁰ Mayo Clinic, Psychiatric Genomics and Pharmacogenomics Program, Rochester, MN, USA.
¹¹ Icahn School of Medicine at Mount Sinai, Department of Neuroscience, New York, NY, USA.
¹² Mayo Clinic, Department of Health Sciences Research, and Department of Psychiatry and Psychology, Rochester, MN, USA.
¹³ Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
¹⁴ Institute of Human Genetics, University of Bonn; and Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
¹⁵ University of Utah, Department of Psychiatry, Salt Lake City, UT, USA.
¹⁶ Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Richmond, VA, USA.
¹⁷ 23andMe, Inc, Mountain View, CA, USA.
¹⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁹ Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Psychotherapy and Psychosomatics, Halle, Germany.
²⁰ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²¹ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
²² Human Genomics Research Group, Department of Biomedicine, University of Basel Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²³ NIH/NIAAA, Laboratory of Neurogenetics, Bethesda, MD, USA.
²⁴ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
²⁵ University of Otago, Christchurch, New Zealand.
²⁶ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
²⁷ Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.
²⁸ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
²⁹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁰ Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
³¹ University of Edinburgh, Division of Psychiatry, Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
³² Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
³³ Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
³⁴ Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center/GGz inGeest, Amsterdam, The Netherlands.
³⁵ Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand.
³⁶ Department of Public Health, University of Helsinki, Helsinki, Finland.
³⁷ Mayo Clinic, Department of Health Sciences Research, Rochester, MN, USA.
³⁸ Washington University School of Medicine, Department of Genetics, St. Louis, MO, USA.
³⁹ University of California San Diego, Department of Psychiatry, San Diego, CA, USA.
⁴⁰ NIH/NIAAA, Office of the Clinical Director, Bethesda, MD, USA.
⁴¹ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
⁴² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴³ Department of Sociology, Harvard University, Cambridge, MA, USA.
⁴⁴ University of Colorado School of Medicine, Department of Pharmacology, Aurora, CO, USA.
⁴⁵ Institute of Behavioral Science and Department of Sociology, University of Colorado, Boulder, CO, USA.
⁴⁶ Mayo Clinic, Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, MN, USA.
⁴⁷ Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Durham, NC, USA.
⁴⁸ Washington University School of Medicine, Department of Medicine and Division of Biostatistics, St. Louis, MO, USA.
⁴⁹ Department of Psychiatry, University of Mainz, Mainz, Germany.
⁵⁰ National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
⁵¹ Stanford University Graduate School of Education, Stanford, CA, USA.
⁵² Mayo Clinic, Department of Psychiatry and Psychology, Rochester, MN, USA.
⁵³ Department of Psychiatry and Psychotherapy, University of Düsseldorf, Düsseldorf, Germany.
⁵⁴ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁵⁵ Max-Planck-Institute of Psychiatry, Munich, Germany.
⁵⁶ University of Minnesota, Department of Psychology, Minneapolis, MN, USA.
⁵⁷ Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
⁵⁸ University of Iowa Roy J and Lucille A Carver College of Medicine, Department of Psychiatry, Iowa City, IA, USA.
⁵⁹ Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁶⁰ Department of Psychiatry, University of Bonn, Bonn, Germany.
⁶¹ Institute for Health and Welfare, Helsinki, Finland.
⁶² Department of Statistical Genetics, Max-Planck-Institute of Psychiatry, Munich, Germany.
⁶³ The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK.
⁶⁴ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶⁵ Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁶⁶ Vitos Hospital Herborn, Department of Psychiatry and Psychotherapy, Herborn, Germany.
⁶⁷ University of Pittsburgh, School of Pharmacy, Pittsburgh, PA, USA.
⁶⁸ Department of Psychiatry and Psychotherapy, University of Regensburg Psychiatric Health Care Aargau, Regensburg, Germany.
⁶⁹ LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Department of Addictive Behaviour and Addiction Medicine, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany.
⁷⁰ Medical Park Chiemseeblick in Bernau-Felden, Chiemsee, Germany.
⁷¹ Psychiatric Hospital, Ludwig-Maximilians-University, Munich, Germany.
⁷² Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
⁷³ University of Utah, Department of Sociology, Salt Lake City, UT, USA.
⁷⁴ University of California, San Diego School of Medicine, Department of Psychology, San Diego, CA, USA.
⁷⁵ NIAAA Intramural Research Program, Bethesda, MD, USA.
⁷⁶ Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
⁷⁷ Department of General Practice and Primary Health Care, University of Helsinki, and National Institute for Health and Welfare, Helsinki, Finland.
⁷⁸ Departments of Neurology, Ophthalmology, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
⁷⁹ Center for Omics Discovery and Epidemiology, Behavioral Health Research Division, RTI International, Research Triangle Park, NC, USA.
⁸⁰ Department of Sociology and Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸¹ University of Connecticut School of Medicine, Department of Psychiatry, Farmington, CT, USA.
⁸² University of Colorado Boulder, Institute for Behavioral Genetics, Boulder, CO, USA.
⁸³ University of Colorado Denver, School of Medicine, Denver, CO, USA.
⁸⁴ RTI International, Fellows Program, Research Triangle Park, NC, USA.
⁸⁵ University of Pennsylvania Perelman School of Medicine, Center for Studies of Addiction, Department of Psychiatry and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
⁸⁶ University of Colorado Boulder, Department of Molecular, Cellular, and Developmental Biology, Boulder, CO, USA.
⁸⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, Sweden.
⁸⁸ Peter Boris Centre for Addictions Research, McMaster University/St. Joseph's Healthcare Hamilton; Michael G. DeGroote Centre for Medicinal Cannabis Research, Hamilton, Ontario, Canada.
⁸⁹ Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
⁹⁰ The Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁹¹ Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany.
⁹² University of California San Diego, Institute for Genomic Medicine, San Diego, CA, USA.
⁹³ Department of Psychological & Brain Sciences, Indiana University Bloomington, Bloomington, IN, USA.
⁹⁴ Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA.
⁹⁵ Departments of Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine, Veterans Affairs Connecticut Healthcare System, New Haven, CT, USA. joel.gelernter@yale.edu.
⁹⁶ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. edenberg@iu.edu.
⁹⁷ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. edenberg@iu.edu.
⁹⁸ Washington University School of Medicine, Department of Psychiatry, St. Louis, MO, USA. Arpana@wustl.edu.

PMID: 30482948
PMCID: PMC6430207
DOI: 10.1038/s41593-018-0275-1

Abstract

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10^-13) and African ancestries (rs2066702; P = 2.2 × 10^-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

PubMed Disclaimer

Figures

**Figure 1:. Manhattan plot of discovery trans-ancestral meta-analysis showing strong evidence for rs1229984 in *ADH1B*.**
Results from the discovery meta-analysis of all cohorts (N_case=14,904, N_control=37,944) for association of genome-wide SNPs with AD under a fixed effects meta-analysis weighted by effective sample size. Dashed red reference line indicates genome-wide significance after correction for multiple testing (p < 5E-8).

**Figure 2:. Regional plots for the *ADH1B* locus (rs1229984) in the trans-ancestral discovery, African-American (AA), and European (EU), meta-analyses.**
Results of fixed effects meta-analysis with effective sample size weights for the *ADH1B* locus in (A) all cohorts (N_case=14,904, N_control=37,944); (B) AA cohorts (N_case=3,335, N_control=2,945); and (C) EU cohorts (N_case=11,569, N_control=34,999). Red reference line indicates the genome-wide significance threshold after correction for multiple testing within each analysis (p < 5E-8). Within ancestry, colored points reflect the degree of LD (pairwise r²) to the index variant (indicated by a purple diamond) in 1000 Genomes Project reference data for individuals of (B) African or (C) European ancestry, respectively. LD structures in the two ancestries differ, so for the trans-ancestral sample (A) LD is not given, indicted by gray points. Two-tailed tests used for all analyses.

**Figure 3:. Genetic correlations between 45 traits and alcohol dependence in Europeans.**
Genetic correlation results from LD score regression (LDSR) with the meta-analysis of AD in unrelated EU individuals (N_case=10,206, N_control=28,480). After Bonferroni correction, significant correlations are observed with 17 traits and disorders (p < 1.1E-3; bold), with nominally significant results for 8 additional traits and disorders (p < .05; italics) based on two-tailed tests of the estimated genetic correlation with block jackknife standard errors. Error bars indicate 95% confidence intervals, with arrows indicating intervals extending above 1 or below −1. Vertical gray reference line corresponds to the null hypothesis of no genetic correlation with AD. Phenotypes are organized by research domain.

See this image and copyright information in PMC

Comment in

Phenotype and Environment Matter: Discovering the Genetic and Epigenetic Architecture of Alcohol Use Disorders.
Pollock JD, Lossie AC. Pollock JD, et al. Am J Psychiatry. 2019 Feb 1;176(2):92-95. doi: 10.1176/appi.ajp.2018.18121364. Am J Psychiatry. 2019. PMID: 30704278 No abstract available.

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Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

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Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

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