6533b7d4fe1ef96bd1262a6c
RESEARCH PRODUCT
Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci
Patricia B. MunroeMuredach P. ReillySuzanne RafeltCaroline S. FoxDiederick E. GrobbeeJana V. Van Vliet-ostaptchoukGeorge Davey SmithIngo RuczinskiHaiqing ShenClara C. ElbersClara C. ElbersPieter A. DoevendansMichael BoehnkeNiek VerweijJohn DaneshArchana TareArchana TareErin N. SmithWilliam C. KnowlerTom R. GauntJessica Van SettenMeena KumariClaire E. HastieJeanne M. MccafferyJoseph T. GlessnerSonia ShahMingyao LiAroon D. HingoraniMarten H. HofkerAnnemieke W M SpijkermanRicha SaxenaRicha SaxenaJohn BarnardRhonda M. Cooper-dehoffMatthijs F.l. MeijsMatthew B. LanktreeGarret A. FitzgeraldMark I. MccarthyMaximilian T. LobmeyerDiane Gilbert-diamondPaul BurtonPeter S. SeverNeil R PoulterBernhard O. BöhmInga PeterPhilippa J. TalmudDavid A. MorrowMary PettingerOlaf H. KlungelJane F. FergusonBraxton D. MitchellMartin FarrallMark C.h. De GrootThomas S. PriceChrista MeisingerSanjey R. PatelLi ZhangNilesh J. SamaniCliona MolonyGünther SilbernagelBrendan J. KeatingIan N. M. DayJutta PalmenMarc S. SabatineDaniel J. RaderM. Hadi ZafarmandJames B. MeigsTaimour Y. LangaeeKandice Kottke-marchantWolfgang KoenigMika KivimäkiStephen S. RichSean P. CurtisBarbara ThorandLisa A. Gilhuijs-pedersonStruan F.a. GrantToby JohnsonThomas IlligMieke D. TripErik P A Van IperenAlan R. ShuldinerBenjamin F. VoightBenjamin F. VoightAlice StantonCecilia E. KimYiran GuoRobert ClarkeGail P. JarvikMark J. CaulfieldJames G. WilsonStephen NewhouseMichael W. SteffesWinfried MärzJessica L. MegaClement E. FurlongRobert A. HegeleEric E. SchadtSandosh PadmanabhanTushar BhangaleJane E. RanchalisDavid AltshulerDavid AltshulerChristopher P. NelsonAnthonius De BoerYan GongW. H. Linda KaoS. J. BielinskiDaphne L. Van Der AJeffery R. O'connellFotios DrenosFlorianne BauerJames S. PankowBerta Almoguera CastilloBerta Almoguera CastilloCarl J. PepineRoy L. SilversteinYun LiOlle MelanderErrol D. CrookQuince GibsonJoseph M. ZmudaDeepak L. BhattYvonne T. Van Der SchouwJens BaumertDenis C. ShieldsPeter S. BraundChristian GiegerSolomon K. MusaniDavid S. SiscovickAshok BalasubramanyamThomas P. CappolaHakon HakonarsonJuan P. CasasJuan P. CasasFolkert W. AsselbergsMarcus E. KleberGerald W. DornJerome I. RotterDebbie A LawlorDanish SaleheenCisca WijmengaAnuj GoelN. Charlotte Onland-moretMarcel BruinenbergTaylor YoungRamakrishnan RajagopalanDonald W. BowdenAsif RasheedAlexander P. ReinerAnders HamstenPaul I.w. De BakkerPaul I.w. De BakkerPaul I.w. De BakkerAnke-hilse Maitland-van Der ZeeAnna F. DominiczakBruce H. R. WolffenbuttelJulie A. JohnsonGordon S. HugginsHareesh R. ChandrupatlaSteve E. HumphriesHugh WatkinsGurunathan MurugesanPim Van Der HarstElisabeth A. Rosenthalsubject
AdultMaleCandidate geneSNP ARRAYAdolescentGenotypeSUSCEPTIBILITY LOCI030209 endocrinology & metabolismGenome-wide association studySingle-nucleotide polymorphismLocus (genetics)BLOOD-PRESSUREBiologyPolymorphism Single NucleotideArticleYoung Adult03 medical and health sciences0302 clinical medicineEthnicityGeneticsHumansEUROPEAN AMERICANSGenetic Predisposition to DiseaseRESOURCE CAREGenetics(clinical)GENOME-WIDE ASSOCIATIONGenetics (clinical)Aged030304 developmental biologyGenetic associationAged 80 and overGeneticsAFRICAN-AMERICANS0303 health sciencesINSULIN-RESISTANCECOMMON VARIANTSMiddle Aged3. Good healthSNP genotypingDiabetes Mellitus Type 2Genetic LociCase-Control StudiesRISK-FACTORSFemaleTCF7L2Follow-Up StudiesGenome-Wide Association StudySNP arraydescription
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10 -9) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10 -6). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10 -7) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10 -15). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10 -8). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups. © 2012 The American Society of Human Genetics.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-03-09 |