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RESEARCH PRODUCT

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

Michiel L. BotsGeorgy BakalkinClaire TroakesGérard WaeberAnna-liisa HartikainenDanielle M. DickKay-tee KhawStéphane CauchiToni-kim ClarkeJian'an LuanJaakko KaprioCharlotte Onland-moretCharlotte Onland-moretYurii S. AulchenkoWolfgang H. SommerBen A. OostraAlberto Fernández-medardeJouke-jan HottengaKari StefanssonAngela DoeringLachlan J. M. CoinKijoung SongIda SurakkSylvane DesrivièresPimphen CharoenPimphen CharoenNicholas G. MartinJacqueline C.m. WittemanJohn C. ChambersTim D. SpectorStéphane LobbensGuangju ZhaiPeter VollenweiderDavid StaceyAnbarasu LourdusamyUlrike HeberleinVictor HesselbrockLeena PeltonenLeena PeltonenJames ScottMiklós PalkovitsAlbert HofmanXin YuanCornelia M. Van DuijnGunter SchumannYvonne T. Van Der SchouwNicole VogelzangsNicole SoranzoNicole SoranzoPaul ElliottBrenda W.j.h. PenninxBrenda W.j.h. PenninxNicholas J. WarehamEugenio SantosSilvia PolidoroDiederick E. GrobbeeNorbert DahmenDaniel F. GudbjartssonDorret I. BoomsmaRainer SpanagelOliver StaehlinAnke TönjesMatthieu MaroteauxAinhoa BilbaoEco J. C. De GeusFrancesca DucciVincent MooserMark I. MccarthyPaolo VineisChristine Cavalcanti-proençaWeihua ZhangNelson B. FreimerRuth J. F. LoosAndres MetspaluTatiana ForoudRudolf A. De BoerThorarinn TyrfingssonAnneli PoutaBeverley BalkauBeverley BalkauMatti IsohanniPaul F. O'reillyMassimo ManginoStephan J. L. BakkerElemi J. BreetveltMarjo-riitta JärvelinTõnu EskoInga ProkopenkoDelphine BeuryErich WichmannGerjan NavisJaana LaitinenJohn WhitfieldKaren H. BergerThorgeir E. ThorgeirssonAlanna C. EastonBrigitte KuehnelUlla SovioCuno S.p.m. UiterwaalUnnur ThorsteinsdottirFazil AlievNajaf AminDale R. NyholtAlejandro NúñezDawn M. WaterworthMattijs E. NumansPim Van Der HarstMichael StumvollHoward J. EdenbergJohannes H. SmitGonneke WillemsenAndrew C. HeathSimonetta GuarreraFulvio RicceriJoline W.j. BeulensGiuseppe MatulloAnokhi Ali KhanJean-antoine GiraultChristian MuellerChristian MuellerJaspal S. KoonerAndré G. UitterlindenJing Hua Zhao

subject

Netherlands Twin Register (NTR)alcohol consumptionPopulationautismSingle-nucleotide polymorphismGenome-wide association studygenome-wide analysis; epidemiologic; transcriptional expression analysis; alcohol consumption; autismBiologyQuantitative trait locus03 medical and health sciences0302 clinical medicineSDG 3 - Good Health and Well-beingADDICTIVE BEHAVIORDEPENDENCEGenotype/dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_medicineSNPeducationGenotyping030304 developmental biologyGenetics0303 health scienceseducation.field_of_studyMultidisciplinaryepidemiologicMENAlcohol Drinking/genetics; Alcohol Drinking/metabolism; Animals; Drosophila melanogaster/genetics; Drosophila melanogaster/metabolism; European Continental Ancestry Group/genetics; Female; Gene Expression Regulation/genetics; Genome-Wide Association Study; Genotype; Humans; Male; Mice; Nuclear Proteins/biosynthesis; Nuclear Proteins/genetics; Polymorphism Single Nucleotide; Proteins/genetics; Proteins/metabolism; Quantitative Trait HeritableBiological Sciencesmedicine.diseaseGENOTYPES3. Good healthDROSOPHILA/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_beingAutismtranscriptional expression analysis030217 neurology & neurosurgerygenome-wide analysis

description

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.

yearjournalcountryeditionlanguage
2011-04-26Proceedings of the National Academy of Sciences of the U.S.A.
10.1073/pnas.1017288108https://doi.org/10.1073/pnas.1017288108