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


Schumann, G; Coin, LJ; Lourdusamy, A; Charoen, P; Berger, KH; Stacey, D; Desrivieres, S; Aliev, FA; Khan, AA; Amin, N; Aulchenko, YS; Bakalkin, G; Bakker, SJ; Balkau, B; Beulens, JW; Bilbao, A; de Boer, RA; Beury, D; Bots, ML; Breetvelt, EJ; Cauchi, S; Cavalcanti-Proenca, C; Chambers, JC; Clarke, TK; Dahmen, N; de Geus, EJ; Dick, D; Ducci, F; Easton, A; Edenberg, HJ; Esk, T; Fernandez-Medarde, A; Foroud, T; Freimer, NB; Girault, JA; Grobbee, DE; Guarrera, S; Gudbjartsson, DF; Hartikainen, AL; Heath, AC; Hesselbrock, V; Hofman, A; Hottenga, JJ; Isohanni, MK; Kaprio, J; Khaw, KT; Kuehnel, B; Laitinen, J; Lobbens, S; Luan, J; Mangino, M; Maroteaux, M; Matullo, G; McCarthy, MI; Mueller, C; Navis, G; Numans, ME; Nunez, A; Nyholt, DR; Onland-Moret, CN; Oostra, BA; O'Reilly, PF; Palkovits, M; Penninx, BW; Polidoro, S; Pouta, A; Prokopenko, I; Ricceri, F; Santos, E; Smit, JH; Soranzo, N; Song, K; Sovio, U; Stumvoll, M; Surakk, I; Thorgeirsson, TE; Thorsteinsdottir, U; Troakes, C; Tyrfingsson, T; Tonjes, A; Uiterwaal, CS; Uitterlinden, AG; van der Harst, P; van der Schouw, YT; Staehlin, O; Vogelzangs, N; Vollenweider, P; Waeber, G; Wareham, NJ; Waterworth, DM; Whitfield, JB; Wichmann, EH; Willemsen, G; Witteman, JC; Yuan, X; Zhai, G; Zhao, JH; Zhang, W; Martin, NG; Metspalu, A; Doering, A; Scott, J; Spector, TD; Loos, RJ; Boomsma, DI; Mooser, V; Peltonen, L; Stefansson, K; van Duijn, CM; Vineis, P; Sommer, WH; Kooner, JS; Spanagel, R; Heberlein, UA; Jarvelin, MR; 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. ISSN 0027-8424 DOI: https://doi.org/10.1073/pnas.1017288108

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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 approximately 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. 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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 21471458
Web of Science ID: 289888500082
URI: http://researchonline.lshtm.ac.uk/id/eprint/853

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