Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Kyle J GaultonTeresa FerreiraYeji LeeAnne RaimondoReedik MägiMichael E ReschenAnubha MahajanAdam LockeN William RaynerNeil RobertsonRobert A ScottInga ProkopenkoLaura J ScottTodd GreenThomas SparsoDorothee ThuillierLoic YengoHarald GrallertSimone WahlMattias FrånbergRona J StrawbridgeHans KestlerHimanshu ChhedaLewin EiseleStefan GustafssonValgerdur SteinthorsdottirGudmar ThorleifssonLu QiLennart C KarssenElisabeth M van LeeuwenSara M WillemsMan LiHan ChenChristian FuchsbergerPhoenix KwanClement MaMichael LindermanYingchang LuSoren K ThomsenJana K RundleNicola L BeerMartijn van de BuntAnil ChaliseyHyun Min KangBenjamin F VoightGonçalo R AbecasisPeter AlmgrenDamiano BaldassarreBeverley BalkauRafn BenediktssonMatthias BlüherHeiner BoeingLori L BonnycastleErwin P BottingerNoël P BurttJason CareyGuillaume CharpentierPeter S ChinesMarilyn C CornelisDavid J CouperAndrew T CrenshawRob M van DamAlex S F DoneyMozhgan DorkhanSarah EdkinsJohan G ErikssonTonu EskoElodie EuryJoão FadistaJason FlannickPierre FontanillasCaroline FoxPaul W FranksKarl GertowChristian GiegerBruna GiganteOmri GottesmanGeorge B GrantNiels GrarupChristopher J GrovesMaija HassinenChristian T HaveChristian HerderOddgeir L HolmenAstradur B HreidarssonSteve E HumphriesDavid J HunterAnne U JacksonAnna JonssonMarit E JørgensenTorben JørgensenWen-Hong L KaoNicola D KerrisonLeena KinnunenNorman KloppAugustine KongPeter KovacsPeter KraftJasmina KravicCordelia LangfordKarin LeanderLiming LiangPeter LichtnerCecilia M LindgrenEero LindholmAllan LinnebergChing-Ti LiuStéphane LobbensJian'an LuanValeriya LyssenkoSatu MännistöOlga McLeodJulia MeyerEvelin MihailovGhazala MirzaThomas W MühleisenMartina Müller-NurasyidCarmen NavarroMarkus M NöthenNikolay N OskolkovKatharine R OwenDomenico PalliSonali PechlivanisLeena PeltonenJohn R B PerryCarl G P PlatouMichael RodenDouglas RuderferDenis RybinYvonne T van der SchouwBengt SennbladGunnar SigurðssonAlena StančákováGerald SteinbachPetter StormKonstantin StrauchHeather M StringhamQi SunBarbara ThorandEmmi TikkanenAnke TonjesJoseph TrakaloElena TremoliTiinamaija TuomiRoman WennauerSteven WiltshireAndrew R WoodEleftheria ZegginiIan DunhamEwan BirneyLorenzo PasqualiJorge FerrerRuth J F LoosJosée DupuisJose C FlorezEric BoerwinkleJames S PankowCornelia van DuijnEric SijbrandsJames B MeigsFrank B HuUnnur ThorsteinsdottirKari StefanssonTimo A LakkaRainer RauramaaMichael StumvollNancy L PedersenLars LindSirkka M Keinanen-KiukaanniemiEeva Korpi-HyövältiTimo E SaaristoJuha SaltevoJohanna KuusistoMarkku LaaksoAndres MetspaluRaimund ErbelKarl-Heinz JöckeSusanne MoebusSamuli RipattiVeikko SalomaaErik IngelssonBernhard O BoehmRichard N BergmanFrancis S CollinsKaren L MohlkeHeikki KoistinenJaakko TuomilehtoKristian HveemInger NjølstadPanagiotis DeloukasPeter J DonnellyTimothy M FraylingAndrew T HattersleyUlf de FaireAnders HamstenThomas IlligAnnette PetersStephane CauchiRob SladekPhilippe FroguelTorben HansenOluf PedersenAndrew D MorrisCollin N A PalmerSekar KathiresanOlle MelanderPeter M NilssonLeif C GroopInês BarrosoClaudia LangenbergNicholas J WarehamChristopher A O'CallaghanAnna L GloynDavid M AltshulerMichael BoehnkeTanya M TeslovichMark I McCarthyAndrew P Morrisnull null

Published in: Nature genetics (2015)

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.