Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7119-24. doi: 10.1073/pnas.1017288108. Epub 2011 Apr 6.

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, Desrivières 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-Proença C, Chambers JC, Clarke TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, Edenberg HJ, Esko T, Fernández-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, Núñez 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, Tönjes 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.

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Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London SE5 8AF, United Kingdom. gunter.schumann@kcl.ac.uk

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Proc Natl Acad Sci U S A. 2011 May 31;108(22):9316. Esk, Tõnu [corrected to Esko, Tõnu].

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 × 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.

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PMCID:: PMC3084048

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Fig. 1.

Functional genetic analysis of AUTS2. (A) Tissue-specific quantitative mRNA expression. Mean mRNA level (SE) of AUTS2, represented by 100/δ Ct, across three independent experiments in human amygdala, frontal cortex, putamen, and liver. Mean Ct values for the housekeeping gene (GAPDH) were similar across tissues: 21.97, 22.42, 21.64, and 19.93, respectively. (B) Genotype-specific quantitative mRNA expression in human prefrontal cortex. Generalized linear model for AUTS2 mRNA levels. Increased AUTS2 mRNA expression observed in carriers of the minor A allele of rs6943555 relative to the major T allele; gene dose effect was significant at P = 0.026. Regression estimates and SEs are shown for the predictors in the model; negative normalized ΔCt values indicate higher expression levels. (C) Line diagram representing tay (dAUTS2) gene region of Drosophila melanogaster. Exons are shown as boxes and positions of P-element insertions by vertical arrows. Direction of transcription is to the right (arrow; http://flybase.org). (D and E) Sensitivity to ethanol sedation of flies with dAUTS2/tay P-element insertion. P-element insertion mutants KG00195 and NP0941, in the 5′-UTR and first intron of tay, respectively, exhibit strongly reduced sensitivity to ethanol sedation relative to the control strain (F_2,23 = 20.7; ***P < 0.001; n = 8). (F and G) Sensitivity to ethanol sedation of flies expressing dAUTS2/tay RNAi in neurons. Flies harboring both the neuronal GAL4 driver elav-GAL4^c155 and the Gal4-responsive UAS-tay^RNAi construct exhibited significantly reduced sensitivity to ethanol sedation compared with control flies harboring either transgene alone (F_2,23 = 7.4; **P = 0.004; n = 8). (H and I) Ethanol absorption of flies with reduced dAUTS2/tay. Internal ethanol concentrations after ethanol exposure for (H) tay RNAi experiment and (I) tay mutants. Neuronal expression of dAUTS2 RNAi did not alter ethanol absorption (F_2,23 = 2.55; P = 0.1; n = 8), and mutants in dAUTS2/tay did not show any significant difference from controls (F_2,11 = 0.252; P = 0.78; n = 4).

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

Proc Natl Acad Sci U S A. 2011 April 26; 2011 May 31;108(17):7119-7124.

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Genome-wide association and genetic functional studies identify autism susceptib...
Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption.
Proc Natl Acad Sci U S A. 2011 Apr 26 ;108(17):7119-24. doi: 10.1073/pnas.1017288108. Epub 2011 Apr 6 .

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