An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

被引：505

作者：

Scott, Robert A. ^{[1
]}

Scott, Laura J. ^{[2
,3
]}

Maegi, Reedik ^{[4
]}

Marullo, Letizia ^{[5
]}

Gaulton, Kyle J. ^{[6
,7
]}

Kaakinen, Marika ^{[8
]}

Pervjakova, Natalia ^{[4
]}

Pers, Tune H. ^{[9
,10
,11
,12
]}

Johnson, Andrew D. ^{[13
]}

Eicher, John D. ^{[13
]}

Jackson, Anne U. ^{[2
,3
]}

Ferreira, Teresa ^{[6
]}

Lee, Yeji ^{[2
]}

Ma, Clement ^{[2
]}

Steinthorsdottir, Valgerdur ^{[14
]}

Thorleifsson, Gudmar ^{[14
]}

Qi, Lu ^{[15
,16
,17
,18
]}

Van Zuydam, Natalie R. ^{[6
]}

Mahajan, Anubha ^{[6
]}

Chen, Han ^{[19
,20
,21
]}

Almgren, Peter ^{[22
]}

Voight, Ben F. ^{[23
,24
,25
]}

Grallert, Harald ^{[26
,28
]}

Mueller-Nurasyid, Martina ^{[29
,30
,31
,32
]}

Ried, Janina S. ^{[29
]}

Rayner, Nigel W. ^{[6
,33
,34
]}

Robertson, Neil ^{[6
,33
]}

Karssen, Lennart C. ^{[35
,36
]}

Van Leeuwen, Elisabeth M. ^{[35
]}

Willems, Sara M. ^{[1
,35
]}

Fuchsberger, Christian ^{[2
]}

Kwan, Phoenix ^{[2
]}

Teslovich, Tanya M. ^{[2
]}

Chanda, Pritam ^{[37
]}

Li, Man ^{[38
]}

Lu, Yingchang ^{[39
,40
]}

Dina, Christian ^{[41
]}

Thuillier, Dorothee ^{[42
,43
]}

Yengo, Loic ^{[42
,43
]}

Jiang, Longda ^{[8
]}

Sparso, Thomas ^{[11
]}

Kestler, Hans A. ^{[44
,45
]}

Chheda, Himanshu ^{[46
]}

Eisele, Lewin ^{[47
]}

Gustafsson, Stefan ^{[48
,49
]}

Franberg, Mattias ^{[50
,51
,52
]}

Strawbridge, Rona J. ^{[50
]}

Benediktsson, Rafn ^{[53
,54
]}

Hreidarsson, Astradur B. ^{[54
]}

Kong, Augustine ^{[14
]}

机构：

[1] Univ Cambridge, MRC Epidemiol Unit, Cambridge, England

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

[3] Ctr Stat Genet, Ann Arbor, MI 48109 USA

[4] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia

[5] Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy

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

[7] Stanford Univ, Dept Genet, Stanford, CA USA

[8] Imperial Coll London, Dept Genom Common Dis, London, England

[9] Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[10] Boston Childrens Hosp, Div Endocrinol, Ctr Basic & Translat Obes Res, Boston, MA USA

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

[12] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark

[13] Natl Heart Lung & Blood Inst, Div Intramural Res, Framingham Heart Study Populat Sci Branch, Framingham, MA USA

[14] Amgen Inc, DECODE genet, Reykjavik, Iceland

[15] Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[16] Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA

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

[18] Harvard Med Sch, Boston, MA USA

[19] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Human Genet Ctr, Human Genet Environm Sci, Houston, TX USA

[20] Human Genet Environm Sci, Dept Epidemiol, Houston, TX USA

[21] Univ Texas Hlth Sci Ctr, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX USA

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

[23] Univ Penn, Perelman Sch Med, Dept Pharm, Philadelphia, PA USA

[24] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA USA

[25] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA USA

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

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

[28] German Ctr Diabet Res, Neuherberg, Germany

[29] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany

[30] Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dep Med 1, Munich, Germany

[31] Ludwig Maximilians Univ Munchen, Inst Med Informat Genet Epidemiol Biometry & Epid, Munich, Germany

[32] Munich Heart Alliance, German Ctr Cardiovasc Dis, Munich, Germany

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

[34] Wellcome Trust Sanger Inst, Hinxton, England

[35] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[36] Polyomica S Hertogenbosch, Amsterdam, Netherlands

[37] Johns Hopkins Univ, High Throughput Biol Ctr, Sch Med, Baltimore, MD USA

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

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

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

[41] Univ Nantes, CNRS, Inst Thorax, Ctr Hosp Univ Nantes, Nantes, France

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

[43] Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France

[44] Leibniz Inst Aging, Fritz Lipmann Inst, Jena, Germany

[45] Univ Ulm, Inst Med Syst Biol, Ulm, Germany

[46] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

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

[48] Uppsala Univ, Dept Med Sci, Mol Epidemiol, Uppsala, Sweden

[49] Uppsala Univ, Dept Sci Life Lab, Mol Epidemiol, Uppsala, Sweden

[50] Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden

来源：

DIABETES | 2017年 / 66卷 / 11期

关键词：

GENETIC ARCHITECTURE; LOW-FREQUENCY; SUSCEPTIBILITY LOCI; FASTING GLUCOSE; RARE VARIANTS; RISK; RECEPTOR; PROVIDES; PATHOPHYSIOLOGY; METAANALYSIS;

D O I：

10.2337/db16-1253

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

引用

页码：2888 / 2902

页数：15

共 50 条

[1] Evaluating empirical bounds on complex disease genetic architecture [J].

Agarwala, Vineeta ;

Flannick, Jason ;

Sunyaev, Shamil ;

Altshuler, David .

NATURE GENETICS, 2013, 45 (12) :1418-U167

[2] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[3] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[4] Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family [J].

Bonnefond, A. ;

Vaillant, E. ;

Philippe, J. ;

Skrobek, B. ;

Lobbens, S. ;

Yengo, L. ;

Huyvaert, M. ;

Cave, H. ;

Busiah, K. ;

Scharfmann, R. ;

Polak, M. ;

Abdul-Rasoul, M. ;

Froguel, P. ;

Vaxillaire, M. .

DIABETES & METABOLISM, 2013, 39 (03) :276-280

[5] Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes [J].

Bonnefond, Amelie ;

Clement, Nathalie ;

Fawcett, Katherine ;

Yengo, Loic ;

Vaillant, Emmanuel ;

Guillaume, Jean-Luc ;

Dechaume, Aurelie ;

Payne, Felicity ;

Roussel, Ronan ;

Czernichow, Sebastien ;

Hercberg, Serge ;

Hadjadj, Samy ;

Balkau, Beverley ;

Marre, Michel ;

Lantieri, Olivier ;

Langenberg, Claudia ;

Bouatia-Naji, Nabila ;

Charpentier, Guillaume ;

Vaxillaire, Martine ;

Rocheleau, Ghislain ;

Wareham, Nicholas J. ;

Sladek, Robert ;

McCarthy, Mark I. ;

Dina, Christian ;

Barroso, Ines ;

Jockers, Ralf ;

Froguel, Philippe .

NATURE GENETICS, 2012, 44 (03) :297-U98

[6] A Genome-Wide Meta-Analysis of Six Type 1 Diabetes Cohorts Identifies Multiple Associated Loci [J].

Bradfield, Jonathan P. ;

Qu, Hui-Qi ;

Wang, Kai ;

Zhang, Haitao ;

Sleiman, Patrick M. ;

Kim, Cecilia E. ;

Mentch, Frank D. ;

Qiu, Haijun ;

Glessner, Joseph T. ;

Thomas, Kelly A. ;

Frackelton, Edward C. ;

Chiavacci, Rosetta M. ;

Imielinski, Marcin ;

Monos, Dimitri S. ;

Pandey, Rahul ;

Bakay, Marina ;

Grant, Struan F. A. ;

Polychronakos, Constantin ;

Hakonarson, Hakon .

PLOS GENETICS, 2011, 7 (09)

[7] Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data [J].

Burgess, Stephen ;

Butterworth, Adam ;

Thompson, Simon G. .

GENETIC EPIDEMIOLOGY, 2013, 37 (07) :658-665

[8] Leveraging Cross- Species Transcription Factor Binding Site Patterns: From Diabetes Risk Loci to Disease Mechanisms [J].

Claussnitzer, Melina ;

Dankel, Simon N. ;

Klocke, Bernward ;

Grallert, Harald ;

Glunk, Viktoria ;

Berulava, Tea ;

Lee, Heekyoung ;

Oskolkov, Nikolay ;

Fadista, Joao ;

Ehlers, Kerstin ;

Wahl, Simone ;

Hoffmann, Christoph ;

Qian, Kun ;

Ronn, Tina ;

Riess, Helene ;

Mueller-Nurasyid, Martina ;

Bretschneider, Nancy ;

Schroeder, Timm ;

Skurk, Thomas ;

Horsthemke, Bernhard ;

Spieler, Derek ;

Klingenspor, Martin ;

Seifert, Martin ;

Kern, Michael J. ;

Mejhert, Niklas ;

Dahlman, Ingrid ;

Hansson, Ola ;

Hauck, Stefanie M. ;

Blueher, Matthias ;

Arner, Peter ;

Groop, Leif ;

Illig, Thomas ;

Suhre, Karsten ;

Hsu, Yi-Hsiang ;

Mellgren, Gunnar ;

Hauner, Hans ;

Laumen, Helmut .

CELL, 2014, 156 (1-2) :343-358

[9] Multi-ethnic genome-wide association study identifies novel locus for type 2 diabetes susceptibility [J].

Cook, James P. ;

Morris, Andrew P. .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2016, 24 (08) :1175-1180

[10] mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer [J].

Dann, Stephen G. ;

Selvaraj, Anand ;

Thomas, George .

TRENDS IN MOLECULAR MEDICINE, 2007, 13 (06) :252-259

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