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 & 96 others Stéphane Cauchi, Christine Cavalcanti-Proença, John C. Chambers, Toni Kim Clarke, Norbert Dahmen, Eco J. De Geus, Danielle Dick, Francesca Ducci, Alanna Easton, Howard 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

Research output: Contribution to journalArticle

172 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 languageEnglish
Pages (from-to)7119-7124
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number17
DOIs
StatePublished - Apr 26 2011

Fingerprint

Genetic Association Studies
Autistic Disorder
Alcohol Drinking
Genome
Genes
Single Nucleotide Polymorphism
Drinking Behavior
Genome-Wide Association Study
Prefrontal Cortex
Drosophila
Meta-Analysis
Down-Regulation
Genotype
Body Weight
Alcohols
Brain
Population

Keywords

  • Epidemiologic
  • Genome-wide analysis
  • Transcriptional expression analysis

ASJC Scopus subject areas

  • General

Cite this

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

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 journalArticle

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, H, 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
Schumann, Gunter ; Coin, Lachlan J. ; Lourdusamy, Anbarasu ; Charoen, Pimphen ; Berger, Karen H. ; Stacey, David ; Desrivières, Sylvane ; Aliev, Fazil A. ; Khan, Anokhi A. ; Amin, Najaf ; Aulchenko, Yurii S. ; Bakalkin, Georgy ; Bakker, Stephan J. ; Balkau, Beverley ; Beulens, Joline W. ; Bilbao, Ainhoa ; De Boer, Rudolf A. ; Beury, Delphine ; Bots, Michiel L. ; Breetvelt, Elemi J. ; Cauchi, Stéphane ; Cavalcanti-Proença, Christine ; Chambers, John C. ; Clarke, Toni Kim ; Dahmen, Norbert ; De Geus, Eco J. ; Dick, Danielle ; Ducci, Francesca ; Easton, Alanna ; Edenberg, Howard ; Esk, Tõnu ; Fernández-Medarde, Alberto ; Foroud, Tatiana ; Freimer, Nelson B. ; Girault, Jean Antoine ; Grobbee, Diederick E. ; Guarrera, Simonetta ; Gudbjartsson, Daniel F. ; Hartikainen, Anna Liisa ; Heath, Andrew C. ; Hesselbrock, Victor ; Hofman, Albert ; Hottenga, Jouke Jan ; Isohanni, Matti K. ; Kaprio, Jaakko ; Khaw, Kay Tee ; Kuehnel, Brigitte ; Laitinen, Jaana ; Lobbens, Stéphane ; Luan, Jian'an ; Mangino, Massimo ; Maroteaux, Matthieu ; Matullo, Giuseppe ; McCarthy, Mark I. ; Mueller, Christian ; Navis, Gerjan ; Numans, Mattijs E. ; Núñez, Alejandro ; Nyholt, Dale R. ; Onland-Moret, Charlotte N. ; Oostra, Ben A. ; O'Reilly, Paul F. ; Palkovits, Miklos ; Penninx, Brenda W. ; Polidoro, Silvia ; Pouta, Anneli ; Prokopenko, Inga ; Ricceri, Fulvio ; Santos, Eugenio ; Smit, Johannes H. ; Soranzo, Nicole ; Song, Kijoung ; Sovio, Ulla ; Stumvoll, Michael ; Surakk, Ida ; Thorgeirsson, Thorgeir E. ; Thorsteinsdottir, Unnur ; Troakes, Claire ; Tyrfingsson, Thorarinn ; Tönjes, Anke ; Uiterwaal, Cuno S. ; Uitterlinden, Andre G. ; Van Der Harst, Pim ; Van Der Schouw, Yvonne T. ; Staehlin, Oliver ; Vogelzangs, Nicole ; Vollenweider, Peter ; Waeber, Gerard ; Wareham, Nicholas J. ; Waterworth, Dawn M. ; Whitfield, John B. ; Wichmann, Erich H. ; Willemsen, Gonneke ; Witteman, Jacqueline C. ; Yuan, Xin ; Zhai, Guangju ; Zhao, Jing H. ; Zhang, Weihua ; Martin, Nicholas G. ; Metspalu, Andres ; Doering, Angela ; Scott, James ; Spector, Tim D. ; Loos, Ruth J. ; Boomsma, Dorret I. ; Mooser, Vincent ; Peltonen, Leena ; Stefansson, Kari ; Van Duijn, Cornelia M. ; Vineis, Paolo ; Sommer, Wolfgang H. ; Kooner, Jaspal S. ; Spanagel, Rainer ; Heberlein, Ulrike A. ; Jarvelin, Marjo Riitta ; Elliott, Paul. / Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 17. pp. 7119-7124.
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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 ∼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",
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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

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

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U2 - 10.1073/pnas.1017288108

DO - 10.1073/pnas.1017288108

M3 - Article

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

SN - 0027-8424

IS - 17

ER -