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

Saxena, R. et al. (2012) Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. American Journal of Human Genetics, 90(3), pp. 410-425. (doi:10.1016/j.ajhg.2011.12.022)

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Publisher's URL: http://dx.doi.org/10.1016/j.ajhg.2011.12.022

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hastie, Dr Claire and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: 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., Bhangale, T., Böhm, B. O., Braund, P. S., Burton, P. R., Chandrupatla, H. R., Clarke, R., Cooper-DeHoff, R. M., Crook, E. D., Davey-Smith, G., Day, I. N., de Boer, A., de Groot, M. C.H., Drenos, F., Ferguson, J., Fox, C. S., Furlong, C. E., Gibson, Q., Gieger, C., Gilhuijs-Pederson, L. A., Glessner, J. T., Goel, A., Gong, Y., Grant, S. F.A., Grobbee, D. E., Hastie, C., Humphries, S. E., Kim, C. E., Kivimaki, M., Kleber, M., Meisinger, C., Kumari, M., Langaee, T. Y., Lawlor, D. A., Li, M., Lobmeyer, M. T., Maitland-van der Zee, A.-H., Meijs, M. F.L., Molony, C. M., Morrow, D. A., Murugesan, G., Musani, S. K., Nelson, C. P., Newhouse, S. J., O'Connell, J. R., Padmanabhan, S., Palmen, J., Patel, S. R., Pepine, C. J., Pettinger, M., Price, T. S., Rafelt, S., Ranchalis, J., Rasheed, A., Rosenthal, E., Ruczinski, I., Shah, S., Shen, H., Silbernagel, G., Smith, E. N., Spijkerman, A. W.M., Stanton, A., Steffes, M. W., Thorand, B., Trip, M., van der Harst, P., van der A, D. L., van Iperen, E. P.A., van Setten, J., van Vliet-Ostaptchouk, J. V., Verweij, N., Wolffenbuttel, B. H.R., Young, T., Zafarmand, M. H., Zmuda, J. M., Boehnke, M., Altshuler, D., McCarthy, M., Kao, W.H. L., Pankow, J. S., Cappola, T. P., Sever, P., Poulter, N., Caulfield, M., Dominiczak, A., Shields, D. C., Bhatt, D. L., Zhang, L., Curtis, S. P., Danesh, J., Casas, J. P., van der Schouw, Y. T., Onland-Moret, N. C., Doevendans, P. A., Dorn, G. W., Farrall, M., FitzGerald, G. A., Hamsten, A., Hegele, R., Hingorani, A. D., Hofker, M. H., Huggins, G. S., Illig, T., Jarvik, G. P., Johnson, J. A., Klungel, O. H., Knowler, W. C., Koenig, W., März, W., Meigs, J. B., Melander, O., Munroe, P. B., Mitchell, B. D., Bielinski, S. J., Rader, D. J., Reilly, M. P., Rich, S. S., Rotter, J. I., Saleheen, D., Samani, N. J., Schadt, E. E., Shuldiner, A. R., Silverstein, R., Kottke-Marchant, K., Talmud, P. J., Watkins, H., Asselbergs, F. W., de Bakker, P. I.W., McCaffery, J., Wijmenga, C., Sabatine, M. S., Wilson, J. G., Reiner, A., Bowden, D. W., Hakonarson, H., Siscovick, D. S., and Keating, B. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Human Genetics
Journal Abbr.:AJHG
Publisher:Elsevier
ISSN:0002-9297
ISSN (Online):1537-6605
Published Online:09 February 2012
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174241United Kingdom Collaborative Study to Identify the Major Genes Responsible for Human Essential Hypertension (BRIGHT)John ConnellMedical Research Council (MRC)G9521010School of Medicine
348311The British genetics of hypertension study - application to enhance TDT and control recruitment for fine mapping genes for hypertensionAnna DominiczakBritish Heart Foundation (BHF)PG/02/128 MCPG1Institute of Cardiovascular and Medical Sciences