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

2018; Nature Portfolio; Volume: 21; Issue: 12 Linguagem: Inglês

10.1038/s41593-018-0275-1

1546-1726

Raymond K. Walters, Renato Polimanti, Emma C. Johnson, Jeanette N. McClintick, Mark J. Adams, Amy Adkins, Fazil Alıev, Silviu‐Alin Bacanu, Anthony Batzler, Sarah Bertelsen, Joanna M. Biernacka, Tim B. Bigdeli, Li‐Shiun Chen, Toni‐Kim Clarke, Yi‐Ling Chou, Franziska Degenhardt, Anna R. Docherty, Alexis C. Edwards, Pierre Fontanillas, Jerome C. Foo, Louis Fox, Josef Frank, Ina Giegling, Scott D. Gordon, Laura M. Hack, Annette M. Hartmann, Sarah M. Hartz, Stefanie Heilmann‐Heimbach, Stefan Herms, Colin A. Hodgkinson, Per Hoffmann, Jouke‐Jan Hottenga, Martin A. Kennedy, Mervi Alanne-Kinnunen, Bettina Konte, Jari Lahti, Marius Lahti‐Pulkkinen, Dongbing Lai, Lannie Ligthart, Anu Loukola, Brion S. Maher, Hamdi Mbarek, Andrew M. McIntosh, Matthew B. McQueen, Jacquelyn L. Meyers, Yuri Milaneschi, Teemu Palviainen, John F. Pearson, Roseann E. Peterson, Samuli Ripatti, Euijung Ryu, Nancy L. Saccone, Jessica E. Salvatore, Sandra Sanchez‐Roige, Melanie L. Schwandt, Richard Sherva, Fabian Streit, Jana Strohmaier, Nathaniel Thomas, Jen‐Chyong Wang, Bradley T. Webb, Robbee Wedow, Leah Wetherill, Amanda G. Wills, Jason D. Boardman, Danfeng Chen, Doo‐Sup Choi, William Copeland, Robert Culverhouse, Norbert Dahmen, Louisa Degenhardt, Benjamin W. Domingue, Sarah L. Elson, Mark A. Frye, Wolfgang Gäbel, Caroline Hayward, Marcus Ising, Margaret A. Keyes, Falk Kiefer, John R. Kramer, Samuel Kuperman, Susanne Lucae, Michael T. Lynskey, Wolfgang Maier, Karl Mann, Satu Männistö, Bertram Müller‐Myhsok, Alison D. Murray, John I. Nürnberger, Aarno Palotie, Ulrich W. Preuss, Katri Räikkönen, Maureen Reynolds, Monika Ridinger, Norbert Scherbaum, Marc A. Schuckit, Michael Soyka, Jens Treutlein, Stephanie H. Witt, Norbert Wodarz, Peter Zill, Daniel E. Adkins, Joseph M. Boden, Dorret I. Boomsma, Laura J. Bierut, Sandra A. Brown, Kathleen K. Bucholz, Sven Cichon, E. Jane Costello, Harriet de Wit, Nancy Diazgranados, Danielle M. Dick, Johan G. Eriksson, Lindsay A. Farrer, Tatiana Foroud, Nathan A. Gillespie, Alison Goate, David Goldman, Richard A. Grucza, Dana B. Hancock, Kathleen Mullan Harris, Andrew C. Heath, Victor Hesselbrock, John K. Hewitt, Christian J. Hopfer, L. John Horwood, William Iacono, Eric O. Johnson, Jaakko Kaprio, Victor M. Karpyak, Kenneth S. Kendler, Henry R. Kranzler, Kenneth Krauter, Paul Lichtenstein, Penelope A. Lind, Matt McGue, James MacKillop, Pamela A. F. Madden, Hermine H. Maes, Patrik K. E. Magnusson, Nicholas G. Martin, Sarah E. Medland, Grant W. Montgomery, Elliot C. Nelson, Markus M. Nöthen, Abraham A. Palmer, Nancy L. Pedersen, Brenda W.J.H. Penninx, Bernice Porjesz, John P. Rice, Marcella Rietschel, Brien P. Riley, Richard J. Rose, Dan Rujescu, Pei‐Hong Shen, Judy L. Silberg, Michael C. Stallings, Ralph E. Tarter, Michael M. Vanyukov, Scott Vrieze, Tamara L. Wall, John B. Whitfield, Hongyu Zhao, Benjamin M. Neale, Joel Gelernter, Howard J. Edenberg, Arpana Agrawal,

Epigenetics and DNA Methylation

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. Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.