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Nat Neurosci. 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.

Walters RK1,2, Polimanti R3, Johnson EC4, McClintick JN5, Adams MJ6, Adkins AE7, Aliev F8, Bacanu SA9, Batzler A10, Bertelsen S11, Biernacka JM12, Bigdeli TB13, Chen LS4, Clarke TK6, Chou YL4, Degenhardt F14, Docherty AR15, Edwards AC16, Fontanillas P17, Foo JC18, Fox L4, Frank J18, Giegling I19, Gordon S20, Hack LM21, Hartmann AM19, Hartz SM4, Heilmann-Heimbach S14, Herms S14,22, Hodgkinson C23, Hoffmann P14,22, Jan Hottenga J24, Kennedy MA25, Alanne-Kinnunen M26, Konte B19, Lahti J27,28, Lahti-Pulkkinen M28, Lai D29, Ligthart L24, Loukola A26, Maher BS30, Mbarek H24, McIntosh AM31, McQueen MB32, Meyers JL33, Milaneschi Y34, Palviainen T26, Pearson JF35, Peterson RE16, Ripatti S1,2,26,36, Ryu E37, Saccone NL38, Salvatore JE8,16, Sanchez-Roige S39, Schwandt M40, Sherva R41, Streit F18, Strohmaier J18, Thomas N7, Wang JC11, Webb BT9, Wedow R1,2,42,43, Wetherill L29, Wills AG44; 23andMe Research Team, Boardman JD45, Chen D2, Choi DS46, Copeland WE47, Culverhouse RC48, Dahmen N49, Degenhardt L50, Domingue BW51, Elson SL17, Frye MA52, Gäbel W53, Hayward C54, Ising M55, Keyes M56, Kiefer F57, Kramer J58, Kuperman S58, Lucae S55, Lynskey MT59, Maier W60, Mann K57, Männistö S61, Müller-Myhsok B62, Murray AD63, Nurnberger JI29,64, Palotie A1,2,26,65, Preuss U19,66, Räikkönen K28, Reynolds MD67, Ridinger M68, Scherbaum N69, Schuckit MA39, Soyka M70,71, Treutlein J18, Witt S18, Wodarz N72, Zill P71, Adkins DE15,73, Boden JM25, Boomsma DI24, Bierut LJ4, Brown SA39,74, Bucholz KK4, Cichon S22, Costello EJ47, de Wit H75, Diazgranados N75, Dick DM7,76, Eriksson JG77, Farrer LA41,78, Foroud TM29, Gillespie NA16, Goate AM11, Goldman D23,40, Grucza RA4, Hancock DB79, Harris KM80, Heath AC4, Hesselbrock V81, Hewitt JK82, Hopfer CJ83, Horwood J25, Iacono W56, Johnson EO84, Kaprio JA26,36, Karpyak VM52, Kendler KS9, Kranzler HR85, Krauter K86, Lichtenstein P87, Lind PA20, McGue M56, MacKillop J88, Madden PAF4, Maes HH89, Magnusson P87, Martin NG20, Medland SE20, Montgomery GW90, Nelson EC4, Nöthen MM91, Palmer AA39,92, Pedersen NL87, Penninx BWJH34, Porjesz B33, Rice JP4, Rietschel M18, Riley BP9, Rose R93, Rujescu D19, Shen PH23, Silberg J16, Stallings MC82, Tarter RE67, Vanyukov MM67, Vrieze S56, Wall TL39, Whitfield JB20, Zhao H94, Neale BM1,2, Gelernter J95, Edenberg HJ96,97, Agrawal A98.

Author information

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.

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.

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

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