Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

Richa Saxena; Clara C. Elbers; Yiran Guo; Inga Peter; Tom R. Gaunt; Jessica L. Mega; Matthew B. Lanktree; Archana Tare; Berta Almoguera Castillo; Yun R. Li; Toby Johnson; Marcel Bruinenberg; Diane Gilbert-Diamond; Ramakrishnan Rajagopalan; Benjamin F. Voight; Ashok Balasubramanyam; John Barnard; Florianne Bauer; Jens Baumert; Tushar Bhangale; Bernhard O. Böhm; Peter S. Braund; Paul R. Burton; Hareesh R. Chandrupatla; Robert Clarke; Rhonda M. Cooper-Dehoff; Errol D. Crook; George Davey-Smith; Ian N. Day; Anthonius De Boer; Mark C.H. De Groot; Fotios Drenos; Jane Ferguson; Caroline S. Fox; Clement E. Furlong; Quince Gibson; Christian Gieger; Lisa A. Gilhuijs-Pederson; Joseph T. Glessner; Anuj Goel; Yan Gong; Struan F.A. Grant; Diederick E. Grobbee; Claire Hastie; Steve E. Humphries; Cecilia E. Kim; Mika Kivimaki; Marcus Kleber; Christa Meisinger; Meena Kumari; Taimour Y. Langaee; Debbie A. Lawlor; Mingyao Li; Maximilian T. Lobmeyer; Anke Hilse Maitland-Van Der Zee; Matthijs F.L. Meijs; Cliona M. Molony; David A. Morrow; Gurunathan Murugesan; Solomon K. Musani; Christopher P. Nelson; Stephen J. Newhouse; Jeffery R. O'Connell; Sandosh Padmanabhan; Jutta Palmen; Sanjey R. Patel; Carl J. Pepine; Mary Pettinger; Thomas S. Price; Suzanne Rafelt; Jane Ranchalis; Asif Rasheed; Elisabeth Rosenthal; Ingo Ruczinski; Sonia Shah; Haiqing Shen; Günther Silbernagel; Erin N. Smith; Annemieke W.M. Spijkerman; Alice Stanton; Michael W. Steffes; Barbara Thorand; Mieke Trip; Pim Van Der Harst; Daphne L. Van Der A; Erik P.A. Van Iperen; Jessica Van Setten; Jana V. Van Vliet-Ostaptchouk; Niek Verweij; Bruce H.R. Wolffenbuttel; Taylor Young; M. Hadi Zafarmand; Joseph M. Zmuda; Michael Boehnke; David Altshuler; Mark McCarthy; W. H.Linda Kao; James S. Pankow; Thomas P. Cappola; Peter Sever; Neil Poulter; Mark Caulfield; Anna Dominiczak; Denis C. Shields; Deepak L. Bhatt; Li Zhang; Sean P. Curtis; John Danesh; Juan P. Casas; Yvonne T. Van Der Schouw; N. Charlotte Onland-Moret; Pieter A. Doevendans; Gerald W. Dorn; Martin Farrall; Garret A. Fitzgerald; Anders Hamsten; Robert Hegele; Aroon D. Hingorani; Marten H. Hofker; Gordon S. Huggins; Thomas Illig; Gail P. Jarvik; Julie A. Johnson; Olaf H. Klungel; William C. Knowler; Wolfgang Koenig; Winfried März; James B. Meigs; Olle Melander; Patricia B. Munroe; Braxton D. Mitchell; Susan J. Bielinski; Daniel J. Rader; Muredach P. Reilly; Stephen S. Rich; Jerome I. Rotter; Danish Saleheen; Nilesh J. Samani; Eric E. Schadt; Alan R. Shuldiner; Roy Silverstein; Kandice Kottke-Marchant; Philippa J. Talmud; Hugh Watkins; Folkert W. Asselbergs; Paul I.W. De Bakker; Jeanne McCaffery; Cisca Wijmenga; Marc S. Sabatine; James G. Wilson; Alex Reiner; Donald W. Bowden; Hakon Hakonarson; David S. Siscovick; Brendan J. Keating

doi:10.1016/j.ajhg.2011.12.022

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

Richa Saxena, Clara C. Elbers, Yiran Guo, Inga Peter, Tom R. Gaunt, Jessica L. Mega, Matthew B. Lanktree, Archana Tare, Berta Almoguera Castillo, Yun R. Li, Toby Johnson, Marcel Bruinenberg, Diane Gilbert-Diamond, Ramakrishnan Rajagopalan, Benjamin F. Voight, Ashok Balasubramanyam, John Barnard, Florianne Bauer, Jens Baumert, Tushar BhangaleBernhard O. Böhm, Peter S. Braund, Paul R. Burton, Hareesh R. Chandrupatla, Robert Clarke, Rhonda M. Cooper-Dehoff, Errol D. Crook, George Davey-Smith, Ian N. Day, Anthonius De Boer, Mark C.H. De Groot, Fotios Drenos, Jane Ferguson, Caroline S. Fox, Clement E. Furlong, Quince Gibson, Christian Gieger, Lisa A. Gilhuijs-Pederson, Joseph T. Glessner, Anuj Goel, Yan Gong, Struan F.A. Grant, Diederick E. Grobbee, Claire Hastie, Steve E. Humphries, Cecilia E. Kim, Mika Kivimaki, Marcus Kleber, Christa Meisinger, Meena Kumari, Taimour Y. Langaee, Debbie A. Lawlor, Mingyao Li, Maximilian T. Lobmeyer, Anke Hilse Maitland-Van Der Zee, Matthijs F.L. Meijs, Cliona M. Molony, David A. Morrow, Gurunathan Murugesan, Solomon K. Musani, Christopher P. Nelson, Stephen J. Newhouse, Jeffery R. O'Connell, Sandosh Padmanabhan, Jutta Palmen, Sanjey R. Patel, Carl J. Pepine, Mary Pettinger, Thomas S. Price, Suzanne Rafelt, Jane Ranchalis, Asif Rasheed, Elisabeth Rosenthal, Ingo Ruczinski, Sonia Shah, Haiqing Shen, Günther Silbernagel, Erin N. Smith, Annemieke W.M. Spijkerman, Alice Stanton, Michael W. Steffes, Barbara Thorand, Mieke Trip, Pim Van Der Harst, Daphne L. Van Der A, Erik P.A. Van Iperen, Jessica Van Setten, Jana V. Van Vliet-Ostaptchouk, Niek Verweij, Bruce H.R. Wolffenbuttel, Taylor Young, M. Hadi Zafarmand, Joseph M. Zmuda, Michael Boehnke, David Altshuler, Mark McCarthy, W. H.Linda Kao, James S. Pankow, Thomas P. Cappola, Peter Sever, Neil Poulter, Mark Caulfield, Anna Dominiczak, Denis C. Shields, Deepak L. Bhatt, Li Zhang, Sean P. Curtis, John Danesh, Juan P. Casas, Yvonne T. Van Der Schouw, N. Charlotte Onland-Moret, Pieter A. Doevendans, Gerald W. Dorn, Martin Farrall, Garret A. Fitzgerald, Anders Hamsten, Robert Hegele, Aroon D. Hingorani, Marten H. Hofker, Gordon S. Huggins, Thomas Illig, Gail P. Jarvik, Julie A. Johnson, Olaf H. Klungel, William C. Knowler, Wolfgang Koenig, Winfried März, James B. Meigs, Olle Melander, Patricia B. Munroe, Braxton D. Mitchell, Susan J. Bielinski, Daniel J. Rader, Muredach P. Reilly, Stephen S. Rich, Jerome I. Rotter, Danish Saleheen, Nilesh J. Samani, Eric E. Schadt, Alan R. Shuldiner, Roy Silverstein, Kandice Kottke-Marchant, Philippa J. Talmud, Hugh Watkins, Folkert W. Asselbergs, Paul I.W. De Bakker, Jeanne McCaffery, Cisca Wijmenga, Marc S. Sabatine, James G. Wilson, Alex Reiner, Donald W. Bowden, Hakon Hakonarson, David S. Siscovick, Brendan J. Keating

Research output: Contribution to journal › Article › peer-review

215 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	410-425
Number of pages	16
Journal	American journal of human genetics
Volume	90
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2011.12.022
State	Published - Mar 9 2012

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10.1016/j.ajhg.2011.12.022

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Saxena, R., Elbers, C. C., Guo, Y., Peter, I., Gaunt, T. R., Mega, J. L., Lanktree, M. B., Tare, A., Castillo, B. A., Li, Y. R., Johnson, T., Bruinenberg, M., Gilbert-Diamond, D., Rajagopalan, R., Voight, B. F., Balasubramanyam, A., Barnard, J., Bauer, F., Baumert, J., ... Keating, B. J. (2012). Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. American journal of human genetics, 90(3), 410-425. https://doi.org/10.1016/j.ajhg.2011.12.022

@article{835636ab9a754f27b3d882041cbcc6d4,

title = "Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci",

abstract = "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.",

author = "Richa Saxena and Elbers, {Clara C.} and Yiran Guo and Inga Peter and Gaunt, {Tom R.} and Mega, {Jessica L.} and Lanktree, {Matthew B.} and Archana Tare and Castillo, {Berta Almoguera} and Li, {Yun R.} and Toby Johnson and Marcel Bruinenberg and Diane Gilbert-Diamond and Ramakrishnan Rajagopalan and Voight, {Benjamin F.} and Ashok Balasubramanyam and John Barnard and Florianne Bauer and Jens Baumert and Tushar Bhangale and B{\"o}hm, {Bernhard O.} and Braund, {Peter S.} and Burton, {Paul R.} and Chandrupatla, {Hareesh R.} and Robert Clarke and Cooper-Dehoff, {Rhonda M.} and Crook, {Errol D.} and George Davey-Smith and Day, {Ian N.} and {De Boer}, Anthonius and {De Groot}, {Mark C.H.} and Fotios Drenos and Jane Ferguson and Fox, {Caroline S.} and Furlong, {Clement E.} and Quince Gibson and Christian Gieger and Gilhuijs-Pederson, {Lisa A.} and Glessner, {Joseph T.} and Anuj Goel and Yan Gong and Grant, {Struan F.A.} and Grobbee, {Diederick E.} and Claire Hastie and Humphries, {Steve E.} and Kim, {Cecilia E.} and Mika Kivimaki and Marcus Kleber and Christa Meisinger and Meena Kumari and Langaee, {Taimour Y.} and Lawlor, {Debbie A.} and Mingyao Li and Lobmeyer, {Maximilian T.} and {Maitland-Van Der Zee}, {Anke Hilse} and Meijs, {Matthijs F.L.} and Molony, {Cliona M.} and Morrow, {David A.} and Gurunathan Murugesan and Musani, {Solomon K.} and Nelson, {Christopher P.} and Newhouse, {Stephen J.} and O'Connell, {Jeffery R.} and Sandosh Padmanabhan and Jutta Palmen and Patel, {Sanjey R.} and Pepine, {Carl J.} and Mary Pettinger and Price, {Thomas S.} and Suzanne Rafelt and Jane Ranchalis and Asif Rasheed and Elisabeth Rosenthal and Ingo Ruczinski and Sonia Shah and Haiqing Shen and G{\"u}nther Silbernagel and Smith, {Erin N.} and Spijkerman, {Annemieke W.M.} and Alice Stanton and Steffes, {Michael W.} and Barbara Thorand and Mieke Trip and {Van Der Harst}, Pim and {Van Der A}, {Daphne L.} and {Van Iperen}, {Erik P.A.} and {Van Setten}, Jessica and {Van Vliet-Ostaptchouk}, {Jana V.} and Niek Verweij and Wolffenbuttel, {Bruce H.R.} and Taylor Young and Zafarmand, {M. Hadi} and Zmuda, {Joseph M.} and Michael Boehnke and David Altshuler and Mark McCarthy and Kao, {W. H.Linda} and Pankow, {James S.} and Cappola, {Thomas P.} and Peter Sever and Neil Poulter and Mark Caulfield and Anna Dominiczak and Shields, {Denis C.} and Bhatt, {Deepak L.} and Li Zhang and Curtis, {Sean P.} and John Danesh and Casas, {Juan P.} and {Van Der Schouw}, {Yvonne T.} and Onland-Moret, {N. Charlotte} and Doevendans, {Pieter A.} and Dorn, {Gerald W.} and Martin Farrall and Fitzgerald, {Garret A.} and Anders Hamsten and Robert Hegele and Hingorani, {Aroon D.} and Hofker, {Marten H.} and Huggins, {Gordon S.} and Thomas Illig and Jarvik, {Gail P.} and Johnson, {Julie A.} and Klungel, {Olaf H.} and Knowler, {William C.} and Wolfgang Koenig and Winfried M{\"a}rz and Meigs, {James B.} and Olle Melander and Munroe, {Patricia B.} and Mitchell, {Braxton D.} and Bielinski, {Susan J.} and Rader, {Daniel J.} and Reilly, {Muredach P.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Danish Saleheen and Samani, {Nilesh J.} and Schadt, {Eric E.} and Shuldiner, {Alan R.} and Roy Silverstein and Kandice Kottke-Marchant and Talmud, {Philippa J.} and Hugh Watkins and Asselbergs, {Folkert W.} and {De Bakker}, {Paul I.W.} and Jeanne McCaffery and Cisca Wijmenga and Sabatine, {Marc S.} and Wilson, {James G.} and Alex Reiner and Bowden, {Donald W.} and Hakon Hakonarson and Siscovick, {David S.} and Keating, {Brendan J.}",

note = "Funding Information: The CARe Consortium wishes to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard University and the Massachusetts Institute of Technology (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Cleveland Family Study (CFS), the Cooperative Study of Sickle Cell Disease (CSSCD), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). R.S. is partially supported by NIDDK NIH R21 (DK089378). C.C.E is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (NWO). Additional acknowledgements for each cohort are listed in the Supplemental Data. Also see the Supplemental Data for conflict-of-interest disclosures for some of the authors. ",

year = "2012",

month = mar,

day = "9",

doi = "10.1016/j.ajhg.2011.12.022",

language = "English",

volume = "90",

pages = "410--425",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

number = "3",

}

Saxena, R, Elbers, CC, Guo, Y, Peter, I, Gaunt, TR, Mega, JL, Lanktree, MB, Tare, A, Castillo, BA, Li, YR, Johnson, T, Bruinenberg, M, Gilbert-Diamond, D, Rajagopalan, R, Voight, BF, Balasubramanyam, A, Barnard, J, Bauer, F, Baumert, J, Bhangale, T, Böhm, BO, Braund, PS, Burton, PR, Chandrupatla, HR, Clarke, R, Cooper-Dehoff, RM, Crook, ED, Davey-Smith, G, Day, IN, De Boer, A, De Groot, MCH, Drenos, F, Ferguson, J, Fox, CS, Furlong, CE, Gibson, Q, Gieger, C, Gilhuijs-Pederson, LA, Glessner, JT, Goel, A, Gong, Y, Grant, SFA, Grobbee, DE, Hastie, C, Humphries, SE, Kim, CE, Kivimaki, M, Kleber, M, Meisinger, C, Kumari, M, Langaee, TY, Lawlor, DA, Li, M, Lobmeyer, MT, Maitland-Van Der Zee, AH, Meijs, MFL, Molony, CM, Morrow, DA, Murugesan, G, Musani, SK, Nelson, CP, Newhouse, SJ, O'Connell, JR, Padmanabhan, S, Palmen, J, Patel, SR, Pepine, CJ, Pettinger, M, Price, TS, Rafelt, S, Ranchalis, J, Rasheed, A, Rosenthal, E, Ruczinski, I, Shah, S, Shen, H, Silbernagel, G, Smith, EN, Spijkerman, AWM, Stanton, A, Steffes, MW, Thorand, B, Trip, M, Van Der Harst, P, Van Der A, DL, Van Iperen, EPA, Van Setten, J, Van Vliet-Ostaptchouk, JV, Verweij, N, Wolffenbuttel, BHR, Young, T, Zafarmand, MH, Zmuda, JM, Boehnke, M, Altshuler, D, McCarthy, M, Kao, WHL, Pankow, JS, Cappola, TP, Sever, P, Poulter, N, Caulfield, M, Dominiczak, A, Shields, DC, Bhatt, DL, Zhang, L, Curtis, SP, Danesh, J, Casas, JP, Van Der Schouw, YT, Onland-Moret, NC, Doevendans, PA, Dorn, GW, Farrall, M, Fitzgerald, GA, Hamsten, A, Hegele, R, Hingorani, AD, Hofker, MH, Huggins, GS, Illig, T, Jarvik, GP, Johnson, JA, Klungel, OH, Knowler, WC, Koenig, W, März, W, Meigs, JB, Melander, O, Munroe, PB, Mitchell, BD, Bielinski, SJ, Rader, DJ, Reilly, MP, Rich, SS, Rotter, JI, Saleheen, D, Samani, NJ, Schadt, EE, Shuldiner, AR, Silverstein, R, Kottke-Marchant, K, Talmud, PJ, Watkins, H, Asselbergs, FW, De Bakker, PIW, McCaffery, J, Wijmenga, C, Sabatine, MS, Wilson, JG, Reiner, A, Bowden, DW, Hakonarson, H, Siscovick, DS & Keating, BJ 2012, 'Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci', American journal of human genetics, vol. 90, no. 3, pp. 410-425. https://doi.org/10.1016/j.ajhg.2011.12.022

TY - JOUR

T1 - Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

AU - Saxena, Richa

AU - Elbers, Clara C.

AU - Guo, Yiran

AU - Peter, Inga

AU - Gaunt, Tom R.

AU - Mega, Jessica L.

AU - Lanktree, Matthew B.

AU - Tare, Archana

AU - Castillo, Berta Almoguera

AU - Li, Yun R.

AU - Johnson, Toby

AU - Bruinenberg, Marcel

AU - Gilbert-Diamond, Diane

AU - Rajagopalan, Ramakrishnan

AU - Voight, Benjamin F.

AU - Balasubramanyam, Ashok

AU - Barnard, John

AU - Bauer, Florianne

AU - Baumert, Jens

AU - Bhangale, Tushar

AU - Böhm, Bernhard O.

AU - Braund, Peter S.

AU - Burton, Paul R.

AU - Chandrupatla, Hareesh R.

AU - Clarke, Robert

AU - Cooper-Dehoff, Rhonda M.

AU - Crook, Errol D.

AU - Davey-Smith, George

AU - Day, Ian N.

AU - De Boer, Anthonius

AU - De Groot, Mark C.H.

AU - Drenos, Fotios

AU - Ferguson, Jane

AU - Fox, Caroline S.

AU - Furlong, Clement E.

AU - Gibson, Quince

AU - Gieger, Christian

AU - Gilhuijs-Pederson, Lisa A.

AU - Glessner, Joseph T.

AU - Goel, Anuj

AU - Gong, Yan

AU - Grant, Struan F.A.

AU - Grobbee, Diederick E.

AU - Hastie, Claire

AU - Humphries, Steve E.

AU - Kim, Cecilia E.

AU - Kivimaki, Mika

AU - Kleber, Marcus

AU - Meisinger, Christa

AU - Kumari, Meena

AU - Langaee, Taimour Y.

AU - Lawlor, Debbie A.

AU - Li, Mingyao

AU - Lobmeyer, Maximilian T.

AU - Maitland-Van Der Zee, Anke Hilse

AU - Meijs, Matthijs F.L.

AU - Molony, Cliona M.

AU - Morrow, David A.

AU - Murugesan, Gurunathan

AU - Musani, Solomon K.

AU - Nelson, Christopher P.

AU - Newhouse, Stephen J.

AU - O'Connell, Jeffery R.

AU - Padmanabhan, Sandosh

AU - Palmen, Jutta

AU - Patel, Sanjey R.

AU - Pepine, Carl J.

AU - Pettinger, Mary

AU - Price, Thomas S.

AU - Rafelt, Suzanne

AU - Ranchalis, Jane

AU - Rasheed, Asif

AU - Rosenthal, Elisabeth

AU - Ruczinski, Ingo

AU - Shah, Sonia

AU - Shen, Haiqing

AU - Silbernagel, Günther

AU - Smith, Erin N.

AU - Spijkerman, Annemieke W.M.

AU - Stanton, Alice

AU - Steffes, Michael W.

AU - Thorand, Barbara

AU - Trip, Mieke

AU - Van Der Harst, Pim

AU - Van Der A, Daphne L.

AU - Van Iperen, Erik P.A.

AU - Van Setten, Jessica

AU - Van Vliet-Ostaptchouk, Jana V.

AU - Verweij, Niek

AU - Wolffenbuttel, Bruce H.R.

AU - Young, Taylor

AU - Zafarmand, M. Hadi

AU - Zmuda, Joseph M.

AU - Boehnke, Michael

AU - Altshuler, David

AU - McCarthy, Mark

AU - Kao, W. H.Linda

AU - Pankow, James S.

AU - Cappola, Thomas P.

AU - Sever, Peter

AU - Poulter, Neil

AU - Caulfield, Mark

AU - Dominiczak, Anna

AU - Shields, Denis C.

AU - Bhatt, Deepak L.

AU - Zhang, Li

AU - Curtis, Sean P.

AU - Danesh, John

AU - Casas, Juan P.

AU - Van Der Schouw, Yvonne T.

AU - Onland-Moret, N. Charlotte

AU - Doevendans, Pieter A.

AU - Dorn, Gerald W.

AU - Farrall, Martin

AU - Fitzgerald, Garret A.

AU - Hamsten, Anders

AU - Hegele, Robert

AU - Hingorani, Aroon D.

AU - Hofker, Marten H.

AU - Huggins, Gordon S.

AU - Illig, Thomas

AU - Jarvik, Gail P.

AU - Johnson, Julie A.

AU - Klungel, Olaf H.

AU - Knowler, William C.

AU - Koenig, Wolfgang

AU - März, Winfried

AU - Meigs, James B.

AU - Melander, Olle

AU - Munroe, Patricia B.

AU - Mitchell, Braxton D.

AU - Bielinski, Susan J.

AU - Rader, Daniel J.

AU - Reilly, Muredach P.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Saleheen, Danish

AU - Samani, Nilesh J.

AU - Schadt, Eric E.

AU - Shuldiner, Alan R.

AU - Silverstein, Roy

AU - Kottke-Marchant, Kandice

AU - Talmud, Philippa J.

AU - Watkins, Hugh

AU - Asselbergs, Folkert W.

AU - De Bakker, Paul I.W.

AU - McCaffery, Jeanne

AU - Wijmenga, Cisca

AU - Sabatine, Marc S.

AU - Wilson, James G.

AU - Reiner, Alex

AU - Bowden, Donald W.

AU - Hakonarson, Hakon

AU - Siscovick, David S.

AU - Keating, Brendan J.

N1 - Funding Information: The CARe Consortium wishes to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard University and the Massachusetts Institute of Technology (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Cleveland Family Study (CFS), the Cooperative Study of Sickle Cell Disease (CSSCD), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). R.S. is partially supported by NIDDK NIH R21 (DK089378). C.C.E is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (NWO). Additional acknowledgements for each cohort are listed in the Supplemental Data. Also see the Supplemental Data for conflict-of-interest disclosures for some of the authors.

PY - 2012/3/9

Y1 - 2012/3/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84862785585&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2011.12.022

DO - 10.1016/j.ajhg.2011.12.022

M3 - Article

C2 - 22325160

AN - SCOPUS:84862785585

VL - 90

SP - 410

EP - 425

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

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