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

G Schumann, LJ Coin, A Lourdusamy, P Charoen, KH Berger, D Stacey, S Desrivieres, FA Aliev, AA Khan, Najaf Amin, YS Aulchenko, G Bakalkin, SJ Bakker, B Balkau, JW Beulens, A Bilbao, RA de Boer, D Beury, ML (Michiel) Bots, EJ BreetveltS Cauchi, C Cavalcanti-Proenca, JC Chambers, TK Clarke, N Dahmen, EJ de Geus, D Dick, F Ducci, A Easton, HJ Edenberg, T Esk, A Fernandez-Medarde, T Foroud, NB Freimer, JA Girault, DE (Diederick) Grobbee, S Guarrera, DF Gudbjartsson, AL Hartikainen, AC Heath, V Hesselbrock, Bert Hofman, JJ (Jouke Jan) Hottenga, MK Isohanni, J Kaprio, KT Khaw, B Kuehnel, J Laitinen, S Lobbens, JA Luan, M Mangino, M Maroteaux, G Matullo, MI McCarthy, C Mueller, G Navis, ME Numans, A Nunez, DR Nyholt, CN Onland-Moret, Ben Oostra, PF O'Reilly, M Palkovits, BW Penninx, S Polidoro, A Pouta, I Prokopenko, F Ricceri, E Santos, JH Smit, N Soranzo, K Song, U Sovio, M Stumvoll, I Surakk, TE Thorgeirsson, U Thorsteinsdottir, C Troakes, T Tyrfingsson, A Tonjes, CS Uiterwaal, André Uitterlinden, P van der Harst, YT van der Schouw, O Staehlin, N Vogelzangs, P Vollenweider, G Waeber, NJ Wareham, DM Waterworth, JB Whitfield, EH Wichmann, G Willemsen, JCM Witteman, X Yuan, GJ Zhai, JH Zhao, WH Zhang, NG Martin, A Metspalu, A Doering, J Scott, TD Spector, RJ Loos, DI Boomsma, V Mooser, L Peltonen, K Stefansson, Cornelia Duijn, P Vineis, WH Sommer, JS Kooner, R Spanagel, UA Heberlein, MR Jarvelin, P 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 similar to 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 languageUndefined/Unknown
Pages (from-to)7119-7124
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of Ame
Volume108
Issue number17
DOIs
Publication statusPublished - 2011

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