Suzuki, KenHatzikotoulas, KonstantinosSoutham, LorraineTaylor, Henry JYin, XianyongLorenz, Kim MMandla, RaviHuerta-Chagoya, AliciaMelloni, Giorgio E MKanoni, StavroulaRayner, Nigel WBocher, OzvanArruda, Ana LuizaSonehara, KyutoNamba, ShinichiLee, Simon S KPreuss, Michael HPetty, Lauren ESchroeder, PhilipVanderwerff, BrettKals, MartBragg, FionaLin, KuangGuo, XiuqingZhang, WeihuaYao, JieKim, Young JinGraff, MariaelisaTakeuchi, FumihikoNano, JanaLamri, AmelNakatochi, MasahiroMoon, SanghoonScott, Robert ACook, James PLee, Jung-JinPan, IanTaliun, DanielParra, Esteban JChai, Jin-FangBielak, Lawrence FTabara, YasuharuHai, YangThorleifsson, GudmarGrarup, NielsSofer, TamarWuttke, MatthiasSarnowski, ChloéGieger, ChristianNousome, DarrylTrompet, StellaKwak, Soo-HeonLong, JirongSun, MengTong, LinChen, Wei-MinNongmaithem, Suraj SNoordam, RaymondLim, Victor J YTam, Claudia H TJoo, Yoonjung YoonieChen, Chien-HsiunRaffield, Laura MPrins, Bram PeterNicolas, AudeYanek, Lisa RChen, GuanjieBrody, Jennifer AKabagambe, EdmondAn, PingXiang, Anny HChoi, Hyeok SunCade, Brian ETan, JingyiBroadaway, K AlaineWilliamson, AliceKamali, ZohaCui, JinruiThangam, ManonanthiniAdair, Linda SAdeyemo, AdebowaleAguilar-Salinas, Carlos AAhluwalia, Tarunveer SAnand, Sonia SBertoni, AlainBork-Jensen, JetteBrandslund, IvanBuchanan, Thomas ABurant, Charles FButterworth, Adam SCanouil, MickaëlChan, Juliana C NChang, Li-ChingChee, Miao-LiChen, JiChen, Shyh-HueiChen, Yuan-TsongChen, ZhengmingChuang, Lee-MingCushman, MaryDanesh, JohnDas, Swapan Kde Silva, H JanakaDedoussis, GeorgeDimitrov, LatchezarDoumatey, Ayo PDu, ShufaDuan, QingEckardt, Kai-UweEmery, Leslie SEvans, Daniel SEvans, Michele KFischer, KristaFloyd, James SFord, IanFranco, Oscar HFrayling, Timothy MFreedman, Barry IGenter, PaulineGerstein, Hertzel CGiedraitis, VilmantasGonzález-Villalpando, ClicerioGonzález-Villalpando, Maria ElenaGordon-Larsen, PennyGross, MyronGuare, Lindsay AHackinger, SophieHakaste, LiisaHan, SoheeHattersley, Andrew THerder, ChristianHorikoshi, MomokoHoward, Annie-GreenHsueh, WillaHuang, MengnaHuang, WeiHung, Yi-JenHwang, Mi YeongHwu, Chii-MinIchihara, SahokoIkram, Mohammad ArfanIngelsson, MartinIslam, Md TariqulIsono, MasatoJang, Hye-MiJasmine, FarzanaJiang, GuozhiJonas, Jost BJørgensen, TorbenKamanu, Frederick KKandeel, Fouad RKasturiratne, AnuradhaniKatsuya, TomohiroKaur, VarinderpalKawaguchi, TakahisaKeaton, Jacob MKho, Abel NKhor, Chiea-ChuenKibriya, Muhammad GKim, Duk-HwanKronenberg, FlorianKuusisto, JohannaLäll, KristiLange, Leslie ALee, Kyung MinLee, Myung-ShikLee, Nanette RLeong, AaronLi, LimingLi, YunLi-Gao, RuifangLigthart, SymenLindgren, Cecilia MLinneberg, AllanLiu, Ching-TiLiu, JianjunLocke, Adam ELouie, TinLuan, Jian'anLuk, Andrea OLuo, XiLv, JunLynch, Julie ALyssenko, ValeriyaMaeda, ShiroMamakou, VasilikiMansuri, Sohail RafikMatsuda, KoichiMeitinger, ThomasMelander, OlleMetspalu, AndresMo, HuanMorris, Andrew DMoura, Filipe ANadler, Jerry LNalls, Michael ANayak, UmaNtalla, IoannaOkada, YukinoriOrozco, LorenaPatel, Sanjay RPatil, SnehalPei, PeiPereira, Mark APeters, AnnettePirie, Fraser JPolikowsky, Hannah GPorneala, BiancaPrasad, GauriRasmussen-Torvik, Laura JReiner, Alexander PRoden, MichaelRohde, RebeccaRoll, KatherynSabanayagam, CharumathiSandow, KevinSankareswaran, AlaguSattar, NaveedSchönherr, SebastianShahriar, MohammadShen, BotongShi, JinxiuShin, Dong MunShojima, NobuhiroSmith, Jennifer ASo, Wing YeeStančáková, AlenaSteinthorsdottir, ValgerdurStilp, Adrienne MStrauch, KonstantinTaylor, Kent DThorand, BarbaraThorsteinsdottir, UnnurTomlinson, BrianTran, Tam CTsai, Fuu-JenTuomilehto, JaakkoTusie-Luna, TeresaUdler, Miriam SValladares-Salgado, Adanvan Dam, Rob Mvan Klinken, Jan BVarma, RohitWacher-Rodarte, NielsWheeler, EleanorWickremasinghe, Ananda Rvan Dijk, Ko WillemsWitte, Daniel RYajnik, Chittaranjan SYamamoto, KenYamamoto, KenichiYoon, KyungheonYu, CanqingYuan, Jian-MinYusuf, SalimZawistowski, MatthewZhang, LiangZheng, WeiRaffel, Leslie JIgase, MichiyaIpp, EliRedline, SusanCho, Yoon ShinLind, LarsProvince, Michael AFornage, MyriamHanis, Craig LIngelsson, ErikZonderman, Alan BPsaty, Bruce MWang, Ya-XingRotimi, Charles NBecker, Diane MMatsuda, FumihikoLiu, YongmeiYokota, MitsuhiroKardia, Sharon L RPeyser, Patricia APankow, James SEngert, James CBonnefond, AmélieFroguel, PhilippeWilson, James GSheu, Wayne H HWu, Jer-YuarnHayes, M GeoffreyMa, Ronald C WWong, Tien-YinMook-Kanamori, Dennis OTuomi, TiinamaijaChandak, Giriraj RCollins, Francis SBharadwaj, DwaipayanParé, GuillaumeSale, Michèle MAhsan, HabibulMotala, Ayesha AShu, Xiao-OuPark, Kyong-SooJukema, J WouterCruz, MiguelChen, Yii-Der IdaRich, Stephen SMcKean-Cowdin, RobertaGrallert, HaraldCheng, Ching-YuGhanbari, MohsenTai, E-ShyongDupuis, JoseeKato, NorihiroLaakso, MarkkuKöttgen, AnnaKoh, Woon-PuayBowden, Donald WPalmer, Colin N AKooner, Jaspal SKooperberg, CharlesLiu, SiminNorth, Kari ESaleheen, DanishHansen, TorbenPedersen, OlufWareham, Nicholas JLee, JuyoungKim, Bong-JoMillwood, Iona YWalters, Robin GStefansson, KariAhlqvist, EmmaGoodarzi, Mark OMohlke, Karen LLangenberg, ClaudiaHaiman, Christopher ALoos, Ruth J FFlorez, Jose CRader, Daniel JRitchie, Marylyn DZöllner, SebastianMägi, ReedikMarston, Nicholas ARuff, Christian Tvan Heel, David AFiner, SarahDenny, Joshua CYamauchi, ToshimasaKadowaki, TakashiChambers, John CNg, Maggie C YSim, XuelingBelow, Jennifer ETsao, Philip SChang, Kyong-MiMcCarthy, Mark IMeigs, James BMahajan, AnubhaSpracklen, Cassandra NMercader, Josep MBoehnke, MichaelRotter, Jerome IVujkovic, MarijanaVoight, Benjamin FMorris, Andrew PZeggini, Eleftheria2024-03-222024-03-222024-03Nature. 2024 Mar;627(8003):347-357.http://hdl.handle.net/20.500.12105/19067Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.engVoRDiabetes Mellitus, Type 2Islets of LangerhansHumansGenome-Wide Association StudyEndothelial CellsGenetic Predisposition to DiseasePolymorphism, Single NucleotideAtribución 4.0 Internacional383742566278003347-35710.1038/s41586-024-07019-61476-4687Natureopen access