Gaulton, Kyle JFerreira, TeresaLee, YejiRaimondo, AnneMägi, ReedikReschen, Michael EMahajan, AnubhaLocke, AdamRayner, N WilliamRobertson, NeilScott, Robert AProkopenko, IngaScott, Laura JGreen, ToddSparso, ThomasThuillier, DorotheeYengo, LoicGrallert, HaraldWahl, SimoneFrånberg, MattiasStrawbridge, Rona JKestler, HansChheda, HimanshuEisele, LewinGustafsson, StefanSteinthorsdottir, ValgerdurThorleifsson, GudmarQi, LuKarssen, Lennart Cvan Leeuwen, Elisabeth MWillems, Sara MLi, ManChen, HanFuchsberger, ChristianKwan, PhoenixMa, ClementLinderman, MichaelLu, YingchangThomsen, Soren KRundle, Jana KBeer, Nicola Lvan de Bunt, MartijnChalisey, AnilKang, Hyun MinVoight, Benjamin FAbecasis, Goncalo RAlmgren, PeterBaldassarre, DamianoBalkau, BeverleyBenediktsson, RafnBlüher, MatthiasBoeing, HeinerBonnycastle, Lori LBorringer, Erwin PBurtt, Noël PCarey, JasonCharpentier, GuillaumeChines, Peter SCornelis, Marilyn CCouper, David JCrenshaw, Andrew TVan Dam, RobDoney, Alex SFDorkhan, MozhganEdkins, SarahEriksson, Johan GEsko, TonuEury, ElodieFadista, JoãoFlannick, JasonFontanillas, PierreFox, CarolineFranks, PaulGertow, KarlGieger, ChristianGigante, BrunaGottesman, OmriGrant, George BGrarup, NielsGroves, Christopher JHassinen, MaijaHave, Christian THerder, ChristianHolmen, Oddgeir LHreidarsson, Astradur BHumphries, Steve EHunter, DavidJackson, Anne UJonsson, AnnaJørgensen, Marit EJørgensen, TorbenKao, Wen-Hong LKerrison, Nicola DKinnunen, LeenaKlopp, NormanKong, AugustineKovacs, PeterKraft, PhillipKravic, JasminaLangford, CordeliaLeander, KarinLiang, LimingLichtner, PeterLindgren, Cecilia MLindholm, EeroLinneberg, AllanLiu, Ching-TiLobbens, StéphaneLuan, Jian’anLyssenko, ValeriyaMӓnnistö, SatuMcLeod, OlgaMeyer, JuliaMihailov, EvelinMirza, GhazalaMühleisen, Thomas WMüller-Nurasyid, MartinaNavarro, CarmenNöthen, Markus MOskolkov, Nikolay NOwen, Katharine RPalli, DomenicoPechlivanis, SonaliPeltonen, LeenaPerry, John RBPlatou, Carl GPRoden, MichaelRuderfer, DouglasRybin, Denisvan der Schouw, Yvonne TSennblad, BengtSigurđsson, GunnarStančáková, AlenaSteinbach, GeraldStorm, PetterStrauch, KonstantinStringham, Heather MSun, QiThorand, BarbaraTikkanen, EmmiTonjes, AnkeTrakalo, JosephTremoli, ElenaTuomi, TiinamaijaWennauer, RomanWiltshire, StevenWood, Andrew RZeggini, EleftheriaDunham, IanBirney, EwanPasquali, LorenzoFerrer, JorgeLoos, Ruth JFDupuis, JoséeFlorez, JoseBoerwinkle, EricPankow, James Svan Duijn, CorneliaSijbrands, EricMeigs, JamesHu, FrankThorsteinsdottir, UnnurStefansson, KariLakka, Timo ARauramaa, RainerStumvoll, MichaelPedersen, Nancy LLind, LarsKeinanen-Kiukaanniemi, Sirkka MKorpi-Hyövӓlti, EevaSaaristo, Timo ESaltevo, JuhaKuusisto, JohannaLaakso, MarkkuMetspalu, AndresErbel, RaimundJöckel, Karl-HeinzMoebus, SusanneRipatti, SamuliSalomaa, VeikkoIngelsson, ErikBoehm, Bernhard OBergman, Richard NCollins, Francis SMohlke, Karen LKoistinen, HeikkiTuomilehto, JaakkoHveem, KristianNjølstad, IngerDeloukas, PanagiotisDonnelly, Peter JFrayling, Timothy MHattersley, Andrew Tde Faire, UlfHamsten, AndersIllig, ThomasPeters, AnnetteCauchi, StephaneSladek, RobFroguel, PhilippeHansen, TorbenPedersen, OlufMorris, Andrew DPalmer, Collin NAKathiresan, SekarMelander, OlleNilsson, Peter MGroop, Leif CBarroso, InêsLangenberg, ClaudiaWareham, Nicholas JO’Callaghan, Christopher AGloyn, Anna LAltshuler, DavidBoehnke, MichaelTeslovich, Tanya MMcCarthy, Mark IMorris, Andrew P2016-06-142015Gaulton, K. J., T. Ferreira, Y. Lee, A. Raimondo, R. Mägi, M. E. Reschen, A. Mahajan, et al. 2015. “Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.” Nature genetics 47 (12): 1415-1425. doi:10.1038/ng.3437. http://dx.doi.org/10.1038/ng.3437.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320459We 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/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association 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 this T2D-risk allele 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.en-USJournal Article2016-06-1410.1038/ng.3437