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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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
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 > School of Cardiovascular & Metabolic Health
Journal Name:American Journal of Human Genetics
Journal Abbr.:AJHG
ISSN (Online):1537-6605
Published Online:09 February 2012
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