An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.
Robert A ScottLaura J ScottReedik MägiLetizia MarulloKyle J GaultonMarika KaakinenNatalia PervjakovaTune H PersAndrew D JohnsonJohn D EicherAnne U JacksonTeresa FerreiraYeji LeeClement MaValgerdur SteinthorsdottirGudmar ThorleifssonLu QiNatalie R Van ZuydamAnubha MahajanHan ChenPeter AlmgrenBen F VoightHarald GrallertMartina Müller-NurasyidJanina S RiedNigel W RaynerNeil RobertsonLennart C KarssenElisabeth M van LeeuwenSara M WillemsChristian FuchsbergerPhoenix KwanTanya M TeslovichPritam ChandaMan LiYingchang LuChristian DinaDorothee ThuillierLoic YengoLongda JiangThomas SparsoHans A KestlerHimanshu ChhedaLewin EiseleStefan GustafssonMattias FrånbergRona J StrawbridgeRafn BenediktssonAstradur B HreidarssonAugustine KongGunnar SigurðssonNicola D KerrisonJian'an LuanLiming LiangThomas MeitingerMichael RodenBarbara ThorandTõnu EskoEvelin MihailovCaroline FoxChing-Ti LiuDenis RybinBo IsomaaValeriya LyssenkoTiinamaija TuomiDavid J CouperJames S PankowNiels GrarupChristian T HaveMarit E JørgensenTorben JørgensenAllan LinnebergMarilyn C CornelisRob M van DamDavid J HunterPeter KraftQi SunSarah EdkinsKatharine R OwenJohn R B PerryAndrew R WoodEleftheria ZegginiJuan Tajes-FernandesGoncalo R AbecasisLori L BonnycastlePeter S ChinesHeather M StringhamHeikki A KoistinenLeena KinnunenBengt SennbladThomas W MühleisenMarkus M NöthenSonali PechlivanisDamiano BaldassarreKarl GertowSteve E HumphriesElena TremoliNorman KloppJulia MeyerGerald SteinbachRoman WennauerJohan G ErikssonSatu MӓnnistöLeena PeltonenEmmi TikkanenGuillaume CharpentierElodie EuryStéphane LobbensBruna GiganteKarin LeanderOlga McLeodErwin P BottingerOmri GottesmanDouglas RuderferMatthias BlüherPeter KovacsAnke TonjesNisa M MaruthurChiara ScapoliRaimund ErbelKarl-Heinz JöckelSusanne MoebusUlf de FaireAnders HamstenMichael StumvollPanagiotis DeloukasPeter J DonnellyTimothy M FraylingAndrew T HattersleySamuli RipattiVeikko SalomaaNancy L PedersenBernhard O BoehmRichard N BergmanFrancis S CollinsKaren L MohlkeJaakko TuomilehtoTorben HansenOluf PedersenInês BarrosoLars LannfeltErik IngelssonLars LindCecilia M LindgrenStephane CauchiPhilippe FroguelRuth J F LoosBeverley BalkauHeiner BoeingPaul W FranksAurelio Barricarte GurreaDomenico PalliYvonne T van der SchouwDavid AltshulerLeif C GroopClaudia LangenbergNicholas J WarehamEric SijbrandsCornelia M van DuijnJose C FlorezJames B MeigsEric BoerwinkleChristian GiegerKonstantin StrauchAndres MetspaluAndrew D MorrisColin N A PalmerFrank B HuUnnur ThorsteinsdottirKari StefanssonJosée DupuisAndrew P MorrisMichael BoehnkeMark I McCarthyInga Prokopenkonull nullPublished in: Diabetes (2017)
To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.