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

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224 Scopus citations


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 languageEnglish (US)
Pages (from-to)410-425
Number of pages16
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - Mar 9 2012

Bibliographical 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.


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