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

被引：302

作者：

Gaulton, Kyle J. ^{[1
,2
]}

Ferreira, Teresa ^{[1
]}

Lee, Yeji ^{[3
]}

Raimondo, Anne ^{[4
]}

Maegi, Reedik ^{[5
]}

Reschen, Michael E. ^{[6
]}

Mahajan, Anubha ^{[1
]}

Locke, Adam ^{[3
]}

Rayner, N. William ^{[1
,4
,7
]}

Robertson, Neil ^{[1
,4
]}

Scott, Robert A. ^{[8
]}

Prokopenko, Inga ^{[9
]}

Scott, Laura J. ^{[3
]}

Green, Todd ^{[10
]}

Sparso, Thomas ^{[11
]}

Thuillier, Dorothee ^{[12
]}

Yengo, Loic ^{[12
]}

Grallert, Harald ^{[13
,14
,15
]}

Wahl, Simone ^{[13
,14
,15
]}

Franberg, Mattias ^{[16
,17
,18
]}

Strawbridge, Rona J. ^{[16
]}

Kestler, Hans ^{[19
,20
]}

Chheda, Himanshu ^{[21
]}

Eisele, Lewin ^{[22
]}

Gustafsson, Stefan ^{[23
]}

Steinthorsdottir, Valgerdur ^{[24
]}

Thorleifsson, Gudmar ^{[24
]}

Qi, Lu ^{[25
,26
,27
,28
,29
]}

Karssen, Lennart C. ^{[30
]}

van Leeuwen, Elisabeth M. ^{[30
]}

Willems, Sara M. ^{[8
,30
]}

Li, Man ^{[31
]}

Chen, Han ^{[32
,33
]}

Fuchsberger, Christian ^{[3
]}

Kwan, Phoenix ^{[3
]}

Ma, Clement ^{[3
]}

Linderman, Michael ^{[34
]}

Lu, Yingchang ^{[35
]}

Thomsen, Soren K. ^{[4
]}

Rundle, Jana K. ^{[4
]}

Beer, Nicola L. ^{[1
,4
]}

van de Bunt, Martijn ^{[1
,4
]}

Chalisey, Anil ^{[6
]}

Kang, Hyun Min ^{[3
]}

Voight, Benjamin F. ^{[36
]}

Abecasis, Goncalo R. ^{[3
]}

Almgren, Peter ^{[37
]}

Baldassarre, Damiano ^{[38
,39
]}

Balkau, Beverley ^{[40
,41
]}

Benediktsson, Rafn ^{[42
,43
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[3] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[4] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[5] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[6] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England

[7] Wellcome Trust Sanger Inst, Hinxton, England

[8] Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England

[9] Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England

[10] Broad Inst Harvard & MIT, Cambridge, MA USA

[11] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[12] European Genom Inst Diabet, Lille Inst Biol, Lille, France

[13] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany

[14] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[15] German Ctr Diabet Res, Neuherberg, Germany

[16] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden

[17] Sci Life Lab, Stockholm, Sweden

[18] Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden

[19] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany

[20] Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany

[21] Finnish Inst Mol Med, Helsinki, Finland

[22] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany

[23] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden

[24] deCODE Genet Amgen Inc, Reykjavik, Iceland

[25] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[26] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[27] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA

[28] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[29] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA

[30] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[31] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[32] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[33] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[34] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[35] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

[36] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA

[37] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden

[38] IRCCS, Ctr Cardiol Monzino, Milan, Italy

[39] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy

[40] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France

[41] Univ Paris 11, UMRS 1018, Villejuif, France

[42] Univ Iceland, Fac Med, Reykjavik, Iceland

[43] Landspitali Univ Hosp, Reykjavik, Iceland

[44] Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany

[45] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany

[46] German Inst Human Nutr, Potsdam, Germany

[47] NHGRI, US NIH, Bethesda, MD 20892 USA

[48] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[49] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France

[50] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 12期

基金：

美国国家卫生研究院; 芬兰科学院; 英国医学研究理事会; 英国惠康基金; 瑞典研究理事会;

关键词：

LARGE-SCALE ASSOCIATION; WIDE ASSOCIATION; GLUCOSE-HOMEOSTASIS; GENOTYPE IMPUTATION; COMMON VARIANTS; GLYCEMIC TRAITS; ALPHA-GENE; RISK LOCI; MUTATIONS; CHROMATIN;

D O I：

10.1038/ng.3437

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1415 / +

页数：14

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