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

作者：Günter Schumann, Lachlan Coin, Anbarasu Lourdusamy, Pimphen Charoen, Karen H. Berger, David Stacey, Sylvane Desrivières, Fazil Alıev, Anokhi Ali Khan, Najaf Amin, Yurii S. Aulchenko, Georgy Bakalkin, Stephan J. L. Bakker, Beverley Balkau, Joline W. J. Beulens, Ainhoa Bilbao, Rudolf A. de Boer, Delphine Beury, Michiel L. Bots, Elemi Breetvelt, Stéphane Cauchi, Christine Cavalcanti-Proença, John C. Chambers, Toni‐Kim Clarke, Norbert Dahmen, Eco J. C. de Geus, Danielle M. Dick, Francesca Ducci, Alanna C. Easton, Howard J. Edenberg, Tõnu Esko, Alberto Fernández‐Medarde, Tatiana Foroud, Nelson B. Freimer, Jean‐Antoine Girault, Diederick E. Grobbee, Simonetta Guarrera, Daníel F. Guðbjartsson, Anna‐Liisa Hartikainen, Andrew C. Heath, Victor Hesselbrock, Albert Hofman, Jouke‐Jan Hottenga, Matti 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, Miklós Palkovits, Brenda W.J.H. Penninx, Silvia Polidoro, Anneli Pouta, Inga Prokopenko, Fulvio Ricceri, Eugenio Santos, Johannes H. Smit, Nicole Soranzo, Kijoung Song, Ulla Sovio, Michael Stümvoll, Ida Surakk, Thorgeir E. Thorgeirsson, Unnur Þorsteinsdóttir, Claire Troakes, Þórarinn Tyrfingsson, Anke Tönjes, Cuno S.P.M. Uiterwaal, André G. Uitterlinden, Pim van der Harst, Yvonne T. van der Schouw, Oliver Staehlin, Nicole Vogelzangs, Péter Vollenweider, Gérard Waeber, Nicholas J. Wareham, Dawn Waterworth, John B. Whitfield, Erich Wichmann, Gonneke Willemsen, Jacqueline C.M. Witteman, Xin Yuan, Guangju Zhai, Wei Zhao, Weihua Zhang, Nicholas G. Martin, Andres Metspalu, Angela Doering, James Scott, Tim D. Spector, Ruth J. F. Loos, Dorret I. Boomsma, Vincent Mooser, Leena Peltonen, Kāri Stefánsson, Cornelia M. van Duijn, Paolo Vineis, Wolfgang H. Sommer, Jaspal S. Kooner, Rainer Spanagel, Ulrike Heberlein, Marjo‐Riitta Järvelin, Paul Elliott · 发表于：Proceedings of the National Academy of Sciences · 年份：2011 · DOI：10.1073/pnas.1017288108 · 被引用次数：270 · 研究领域：Autism Spectrum Disorder Research、Genetic Mapping and Diversity in Plants and Animals、Genetic Associations and Epidemiology

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 × 10(-8) to P = 4 × 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. Down-regulation 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.