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Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

Saxena, Richa; Elbers, Clara C.; Guo, Yiran; Peter, Inga; Gaunt, Tom R.; Mega, Jessica L.; Lanktree, Matthew B.; Tare, Archana; Almoguera Castillo, Berta and Li, Yun R., et al. (2012) In American Journal of Human Genetics 90(3). p.410-425
Abstract
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 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... (More)
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 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 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 x 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 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 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 x 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. (Less)
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American Journal of Human Genetics
volume
90
issue
3
pages
410 - 425
publisher
Cell Press
external identifiers
  • wos:000301762800007
  • scopus:84862785585
ISSN
0002-9297
DOI
10.1016/j.ajhg.2011.12.022
language
English
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yes
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1861d0fd-81d5-484b-9c43-2f53fa5186e7 (old id 2591146)
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2012-06-01 09:41:53
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@article{1861d0fd-81d5-484b-9c43-2f53fa5186e7,
  abstract     = {To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 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 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p &lt; 2.4 x 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 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 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 x 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       = {Saxena, Richa and Elbers, Clara C. and Guo, Yiran and Peter, Inga and Gaunt, Tom R. and Mega, Jessica L. and Lanktree, Matthew B. and Tare, Archana and Almoguera Castillo, Berta and Li, Yun R. and Johnson, Toby and Bruinenberg, Marcel and Gilbert-Diamond, Diane and Rajagopalan, Ramakrishnan and Voight, Benjamin F. and Balasubramanyam, Ashok and Barnard, John and Bauer, Florianne and Baumert, Jens and Bhangale, Tushar and Boehm, Bernhard O. and Braund, Peter S. and Burton, Paul R. and Chandrupatla, Hareesh R. and Clarke, Robert and Cooper-DeHoff, Rhonda M. and Crook, Errol D. and Davey-Smith, George and Day, Ian N. and de Boer, Anthonius and de Groot, Mark C. H. and Drenos, Fotios and Ferguson, Jane and Fox, Caroline S. and Furlong, Clement E. and Gibson, Quince and Gieger, Christian and Gilhuijs-Pederson, Lisa A. and Glessner, Joseph T. and Goel, Anuj and Gong, Yan and Grant, Struan F. A. and Grobbee, Diederick E. and Hastie, Claire and Humphries, Steve E. and Kim, Cecilia E. and Kivimaki, Mika and Kleber, Marcus and Meisinger, Christa and Kumari, Meena and Langaee, Taimour Y. and Lawlor, Debbie A. and Li, Mingyao 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 Murugesan, Gurunathan and Musani, Solomon K. and Nelson, Christopher P. and Newhouse, Stephen J. and O'Connell, Jeffery R. and Padmanabhan, Sandosh and Palmen, Jutta and Patel, Sanjey R. and Pepine, Carl J. and Pettinger, Mary and Price, Thomas S. and Rafelt, Suzanne and Ranchalis, Jane and Rasheed, Asif and Rosenthal, Elisabeth and Ruczinski, Ingo and Shah, Sonia and Shen, Haiqing and Silbernagel, Guenther and Smith, Erin N. and Spijkerman, Annemieke W. M. and Stanton, Alice and Steffes, Michael W. and Thorand, Barbara and Trip, Mieke 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 Verweij, Niek and Wolffenbuttel, Bruce H. R. and Young, Taylor and Zafarmand, M. Hadi and Zmuda, Joseph M. and Boehnke, Michael and Altshuler, David and McCarthy, Mark and Kao, W. H. Linda and Pankow, James S. and Cappola, Thomas P. and Sever, Peter and Poulter, Neil and Caulfield, Mark and Dominiczak, Anna and Shields, Denis C. and Bhatt, Deepak L. and Zhang, Li and Curtis, Sean P. and Danesh, John and Casas, Juan P. and van der Schouw, Yvonne T. and Onland-Moret, N. Charlotte and Doevendans, Pieter A. and Dorn II, Gerald W. and Farrall, Martin and FitzGerald, Garret A. and Hamsten, Anders and Hegele, Robert and Hingorani, Aroon D. and Hofker, Marten H. and Huggins, Gordon S. and Illig, Thomas and Jarvik, Gail P. and Johnson, Julie A. and Klungel, Olaf H. and Knowler, William C. and Koenig, Wolfgang and Maerz, Winfried and Meigs, James B. and Melander, Olle 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 Saleheen, Danish and Samani, Nilesh J. and Schadt, Eric E. and Shuldiner, Alan R. and Silverstein, Roy and Kottke-Marchant, Kandice and Talmud, Philippa J. and Watkins, Hugh and Asselbergs, Folkert W. and de Bakker, Paul I. W. and McCaffery, Jeanne and Wijmenga, Cisca and Sabatine, Marc S. and Wilson, James G. and Reiner, Alex and Bowden, Donald W. and Hakonarson, Hakon and Siscovick, David S. and Keating, Brendan J.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {3},
  pages        = {410--425},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2011.12.022},
  volume       = {90},
  year         = {2012},
}