Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Gunter Schumann, Lachlan J. Coin, Anbarasu Lourdusamy, Pimphen Charoen, Karen H. Berger, David Stacey, Sylvane Desrivières, Fazil A. Aliev, Anokhi A. Khan, Najaf Amin, Yurii S. Aulchenko, Georgy Bakalkin, Stephan J. Bakker, Beverley Balkau, Joline W. Beulens, Ainhoa Bilbao, Rudolf A. De Boer, Delphine Beury, Michiel L. Bots, Elemi J. BreetveltStéphane Cauchi, Christine Cavalcanti-Proença, John C. Chambers, Toni Kim Clarke, Norbert Dahmen, Eco J. De Geus, Danielle Dick, Francesca Ducci, Alanna Easton, Howard J. Edenberg, Tõnu Esk, Alberto Fernández-Medarde, Tatiana Foroud, Nelson B. Freimer, Jean Antoine Girault, Diederick E. Grobbee, Simonetta Guarrera, Daniel F. Gudbjartsson, Anna Liisa Hartikainen, Andrew C. Heath, Victor Hesselbrock, Albert Hofman, Jouke Jan Hottenga, Matti K. Isohanni, Jaakko Kaprio, Kay Tee Khaw, Brigitte Kuehnel, Jaana Laitinen, Stéphane Lobbens, Jian'an Luan, Massimo Mangino, Matthieu Maroteaux, Giuseppe Matullo, Mark I. McCarthy, Christian Mueller, Gerjan Navis, Mattijs E. Numans, Alejandro Núñez, Dale R. Nyholt, Charlotte N. Onland-Moret, Ben A. Oostra, Paul F. O'Reilly, Miklos Palkovits, Brenda W. Penninx, Silvia Polidoro, Anneli Pouta, Inga Prokopenko, Fulvio Ricceri, Eugenio Santos, Johannes H. Smit, Nicole Soranzo, Kijoung Song, Ulla Sovio, Michael Stumvoll, Ida Surakk, Thorgeir E. Thorgeirsson, Unnur Thorsteinsdottir, Claire Troakes, Thorarinn Tyrfingsson, Anke Tönjes, Cuno S. Uiterwaal, Andre G. Uitterlinden, Pim Van Der Harst, Yvonne T. Van Der Schouw, Oliver Staehlin, Nicole Vogelzangs, Peter Vollenweider, Gerard Waeber, Nicholas J. Wareham, Dawn M. Waterworth, John B. Whitfield, Erich H. Wichmann, Gonneke Willemsen, Jacqueline C. Witteman, Xin Yuan, Guangju Zhai, Jing H. Zhao, Weihua Zhang, Nicholas G. Martin, Andres Metspalu, Angela Doering, James Scott, Tim D. Spector, Ruth J. Loos, Dorret I. Boomsma, Vincent Mooser, Leena Peltonen, Kari Stefansson, Cornelia M. Van Duijn, Paolo Vineis, Wolfgang H. Sommer, Jaspal S. Kooner, Rainer Spanagel, Ulrike A. Heberlein, Marjo Riitta Jarvelin, Paul Elliott

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Abstract

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10-8 to P = 4 x 10-9). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Original languageEnglish
Pages (from-to)7119-7124
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number17
DOIs
Publication statusPublished - ápr. 26 2011

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    Schumann, G., Coin, L. J., Lourdusamy, A., Charoen, P., Berger, K. H., Stacey, D., Desrivières, S., Aliev, F. A., Khan, A. A., Amin, N., Aulchenko, Y. S., Bakalkin, G., Bakker, S. J., Balkau, B., Beulens, J. W., Bilbao, A., De Boer, R. A., Beury, D., Bots, M. L., ... Elliott, P. (2011). Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proceedings of the National Academy of Sciences of the United States of America, 108(17), 7119-7124. https://doi.org/10.1073/pnas.1017288108