Abstract
Original language | English |
---|---|
Pages (from-to) | 410-425 |
Journal | American journal of human genetics |
Volume | 90 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2012 |
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In: American journal of human genetics, Vol. 90, No. 3, 2012, p. 410-425.
Research output: Contribution to journal › Article › Academic › peer-review
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 - Bhatt, Deepak
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 - Asselbergs, Folkert
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.
PY - 2012
Y1 - 2012
N2 - 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
AB - 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
U2 - https://doi.org/10.1016/j.ajhg.2011.12.022
DO - https://doi.org/10.1016/j.ajhg.2011.12.022
M3 - Article
C2 - 22325160
SN - 0002-9297
VL - 90
SP - 410
EP - 425
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -