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.
Bibliographical noteFunding Information:
L.J.B., A.M.G., J.P.R., J.-C.W. and the spouse of N.L.S. are listed as inventors on Issued US Patent 8080,371, “Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. N.W. has received funding from the German Research Foundation (DFG) and Federal Ministry of Education and Research Germany (BMBF); he has received speaker’s honoraria and travel funds from Janssen-Cilag and Indivior. He took part in industry-sponsored multicenter randomized trials by D&A Pharma and Lundbeck. M. Ridinger received compensation from Lundbeck Switzerland and Lundbeck institute for advisory boards and expert meetings, and from Lundbeck and Lilly Suisse for workshops and presentations. K.M. received honoraria from Lundbeck, Pfizer, Novartis, and AbbVie. K.M. also received Honoraria (Advisory Board) from Lundbeck and Pfizer and speaker fees from Janssen Cilag. H.K. has been an advisory board member, consultant, or continuing medical education speaker for Indivior, Lundbeck, and Otsuka. He is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was sponsored in the past three years by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. H.K. and J.G. are named as inventors on PCT patent application #15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed 24 January 2018. P.F., S.L.E., and members of the 23andMe Research Team are employees of 23andMe. M.A.F. has received grant support from Assurex Health, Mayo Foundation, Myriad, NIAAA, National Institute of Mental Health (NIMH), and Pfizer; he has been a consultant for Intra-Cellular Therapies, Inc., Janssen, Mitsubishi Tanabe Pharma Corporation, Myriad, Neuralstem Inc., Otsuka American Pharmaceutical, Sunovion, and Teva Pharmaceuticals. H.d.W. has received support from Insys Therapeutics and Indivior for studies unrelated to this project, and she has consulted for Marinus and Jazz Pharmaceuticals, also unrelated to this project. T.L.W. has previously received funds from ABMRF. J.N. is an investigator for Janssen and Assurex. M.M.N. has received honoraria from the Lundbeck Foundation and the Robert Bosch Stiftung for membership on advisory boards. M. Ridinger has received honoraria from Lundbeck Switzerland and the Lundbeck Institute for membership of advisory boards and participation in expert meetings, and from Lundbeck and Lilly Suisse for workshops and presentations. N.S. has received honoraria from Abbvie, Sanofi-Aventis, Reckitt Benckiser, Indivior, Lundbeck, and Janssen-Cilag for advisory board membership and the preparation of lectures, manuscripts, and educational materials. Since 2013, N.S. has also participated in clinical trials financed by Reckitt Benckiser and Indivior. N.W. received speaker’s honoraria and travel expenses from Janssen-Cilag and Indivior; has also participated in industry-sponsored multicenter randomized trials conducted by D&A Pharma and Lundbeck. W.G. has received symposia support from Janssen-Cilag GmbH, Neuss, Lilly Deutschland GmbH, Bad Homburg, and Servier, Munich, and is a member of the Faculty of the Lundbeck International Neuroscience Foundation (LINF), Denmark. J.A.K. has provided consultations on nicotine dependence for Pfizer (Finland) 2012–2015. In the past three years, L.D. has received investigator-initiated untied educational grants for studies of opioid medications in Australia from Indivior, Mundipharma, and Seqirus. B.M.N. is a member of the scientific advisory board for Deep Genomics and has consulted for Camp4 Therapeutics Corporation, Merck & Co., and Avanir Pharmaceuticals, Inc. A.A. previously received peer-reviewed funding and travel reimbursement from ABMRF for unrelated research.
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