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. Breetvelt; Stéphane 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

doi:10.1073/pnas.1017288108

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. Breetvelt

Stéphane 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

^*Corresponding author for this work

Medical Research Council-Social, Genetic and Developmental Psychiatry Centre
King's College London
Department of Epidemiology and Biostatistics
Imperial College London
Department of Tropical Hygiene
Mahidol University
Imperial College Healthcare NHS Trust
University of California at San Francisco
Virginia Commonwealth University
Genetic Epidemiology Unit
Erasmus University Rotterdam
Department of Pharmaceutical Biosciences
Uppsala University
Department of Internal Medicine
University of Groningen
Institut national de la santé et de la recherche médicale
Université Paris-Saclay
Utrecht University
Department of Psychopharmacology
Zentralinstitut fur Seelische Gesundheit
Department of Genomics and Molecular Physiology of Metabolic Diseases
CNRS
Department of Psychiatry
Department of Psychiatry and Psychotherapy
Johannes Gutenberg University Mainz
Department of Medical and Molecular Genetics
Indiana University-Purdue University Indianapolis
Department of Biotechnology
University of Tartu
Estonian Genome Project
University of Tartu
Comision de Investigaciones Cientificas de la Provincia de Buenos Aires
Universidad de Salamanca
University of California at Los Angeles
Institut du Fer à Moulin
Institute for Scientific Interchange Foundation
University of Iceland
Institute of Clinical Medicine
University of Oulu
Department of Psychiatry
Washington University St. Louis
University of Connecticut
Vrije Universiteit Amsterdam
Department of Public Health
University of Helsinki
Department of Mental Health and Alcohol Abuse Services
National Institute for Health and Welfare
Department of Public Health and Primary Care
University of Cambridge
Institute of Epidemiology
Helmholtz Zentrum München - German Research Center for Environmental Health
Finnish Institute of Occupational Health
Department of Twin Research and Genetic Epidemiology
Institute for Scientific Information Foundation
University of Turin
University of Oxford
Department of Psychiatry and Psychotherapy
Friedrich-Alexander University Erlangen-Nürnberg
Queensland Institute of Medical Research
Department of Medical Genetics
Semmelweis University
Department of Psychiatry
VU University Medical Center
Leiden University
Wellcome Trust Sanger Institute
Genetics Division
GlaxoSmithKline
Department of Medicine
Leipzig University
Leipzig Research Centre for Modern Diseases (LIFE)
Vogur Samtök Áhugafólks um Áfengis Addiction Treatment Center
Coordination Centre for Clinical Trials
Department of Internal Medicine
Department of Medicine
University of Lausanne
Institute of Medical Informatics
Ludwig Maximilian University of Munich
Department of Biological Psychology
Department of Epidemiology
Institute of Health Sciences
Department of Epidemiology and Biostatistics

Research output: Contribution to journal › Article › peer-review

234 Citations (Scopus)

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 language	English
Pages (from-to)	7119-7124
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	17
DOIs	https://doi.org/10.1073/pnas.1017288108
Publication status	Published - 26 Apr 2011
Externally published	Yes

Keywords

Epidemiologic
Genome-wide analysis
Transcriptional expression analysis

Access to Document

10.1073/pnas.1017288108

Cite this

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

@article{60724bec172e41518cbb70faf2c96272,

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

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.",

keywords = "Epidemiologic, Genome-wide analysis, Transcriptional expression analysis",

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

year = "2011",

month = apr,

day = "26",

doi = "10.1073/pnas.1017288108",

language = "English",

volume = "108",

pages = "7119--7124",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "17",

}

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, Esk, 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 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, vol. 108, no. 17, pp. 7119-7124. https://doi.org/10.1073/pnas.1017288108

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. / Schumann, Gunter; Coin, Lachlan J.; Lourdusamy, Anbarasu et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 17, 26.04.2011, p. 7119-7124.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

AU - Schumann, Gunter

AU - Coin, Lachlan J.

AU - Lourdusamy, Anbarasu

AU - Charoen, Pimphen

AU - Berger, Karen H.

AU - Stacey, David

AU - Desrivières, Sylvane

AU - Aliev, Fazil A.

AU - Khan, Anokhi A.

AU - Amin, Najaf

AU - Aulchenko, Yurii S.

AU - Bakalkin, Georgy

AU - Bakker, Stephan J.

AU - Balkau, Beverley

AU - Beulens, Joline W.

AU - Bilbao, Ainhoa

AU - De Boer, Rudolf A.

AU - Beury, Delphine

AU - Bots, Michiel L.

AU - Breetvelt, Elemi J.

AU - Cauchi, Stéphane

AU - Cavalcanti-Proença, Christine

AU - Chambers, John C.

AU - Clarke, Toni Kim

AU - Dahmen, Norbert

AU - De Geus, Eco J.

AU - Dick, Danielle

AU - Ducci, Francesca

AU - Easton, Alanna

AU - Edenberg, Howard J.

AU - Esk, Tõnu

AU - Fernández-Medarde, Alberto

AU - Foroud, Tatiana

AU - Freimer, Nelson B.

AU - Girault, Jean Antoine

AU - Grobbee, Diederick E.

AU - Guarrera, Simonetta

AU - Gudbjartsson, Daniel F.

AU - Hartikainen, Anna Liisa

AU - Heath, Andrew C.

AU - Hesselbrock, Victor

AU - Hofman, Albert

AU - Hottenga, Jouke Jan

AU - Isohanni, Matti K.

AU - Kaprio, Jaakko

AU - Khaw, Kay Tee

AU - Kuehnel, Brigitte

AU - Laitinen, Jaana

AU - Lobbens, Stéphane

AU - Luan, Jian'an

AU - Mangino, Massimo

AU - Maroteaux, Matthieu

AU - Matullo, Giuseppe

AU - McCarthy, Mark I.

AU - Mueller, Christian

AU - Navis, Gerjan

AU - Numans, Mattijs E.

AU - Núñez, Alejandro

AU - Nyholt, Dale R.

AU - Onland-Moret, Charlotte N.

AU - Oostra, Ben A.

AU - O'Reilly, Paul F.

AU - Palkovits, Miklos

AU - Penninx, Brenda W.

AU - Polidoro, Silvia

AU - Pouta, Anneli

AU - Prokopenko, Inga

AU - Ricceri, Fulvio

AU - Santos, Eugenio

AU - Smit, Johannes H.

AU - Soranzo, Nicole

AU - Song, Kijoung

AU - Sovio, Ulla

AU - Stumvoll, Michael

AU - Surakk, Ida

AU - Thorgeirsson, Thorgeir E.

AU - Thorsteinsdottir, Unnur

AU - Troakes, Claire

AU - Tyrfingsson, Thorarinn

AU - Tönjes, Anke

AU - Uiterwaal, Cuno S.

AU - Uitterlinden, Andre G.

AU - Van Der Harst, Pim

AU - Van Der Schouw, Yvonne T.

AU - Staehlin, Oliver

AU - Vogelzangs, Nicole

AU - Vollenweider, Peter

AU - Waeber, Gerard

AU - Wareham, Nicholas J.

AU - Waterworth, Dawn M.

AU - Whitfield, John B.

AU - Wichmann, Erich H.

AU - Willemsen, Gonneke

AU - Witteman, Jacqueline C.

AU - Yuan, Xin

AU - Zhai, Guangju

AU - Zhao, Jing H.

AU - Zhang, Weihua

AU - Martin, Nicholas G.

AU - Metspalu, Andres

AU - Doering, Angela

AU - Scott, James

AU - Spector, Tim D.

AU - Loos, Ruth J.

AU - Boomsma, Dorret I.

AU - Mooser, Vincent

AU - Peltonen, Leena

AU - Stefansson, Kari

AU - Van Duijn, Cornelia M.

AU - Vineis, Paolo

AU - Sommer, Wolfgang H.

AU - Kooner, Jaspal S.

AU - Spanagel, Rainer

AU - Heberlein, Ulrike A.

AU - Jarvelin, Marjo Riitta

AU - Elliott, Paul

PY - 2011/4/26

Y1 - 2011/4/26

N2 - 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.

AB - 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.

KW - Epidemiologic

KW - Genome-wide analysis

KW - Transcriptional expression analysis

UR - https://www.scopus.com/pages/publications/79955569025

U2 - 10.1073/pnas.1017288108

DO - 10.1073/pnas.1017288108

M3 - Article

C2 - 21471458

AN - SCOPUS:79955569025

SN - 0027-8424

VL - 108

SP - 7119

EP - 7124

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 17

ER -

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

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