Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci Academic Article uri icon

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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.

authors

  • Saxena, Richa
  • Elbers, Clara C
  • Guo, Yiran
  • Peter, Inga
  • Gaunt, Tom R
  • Mega, Jessica L
  • Lanktree, Matthew
  • Tare, Archana
  • Castillo, Berta Almoguera
  • Li, Yun R
  • Johnson, Toby
  • Bruinenberg, Marcel
  • Gilbert-Diamond, Diane
  • Rajagopalan, Ramakrishnan
  • Voight, Benjamin F
  • Balasubramanyam, Ashok
  • Barnard, John
  • Bauer, Florianne
  • Baumert, Jens
  • Bhangale, Tushar
  • Böhm, Bernhard O
  • Braund, Peter S
  • Burton, Paul R
  • Chandrupatla, Hareesh R
  • Clarke, Robert
  • Cooper-DeHoff, Rhonda M
  • Crook, Errol D
  • Davey-Smith, George
  • Day, Ian N
  • de Boer, Anthonius
  • de Groot, Mark CH
  • Drenos, Fotios
  • Ferguson, Jane
  • Fox, Caroline S
  • Furlong, Clement E
  • Gibson, Quince
  • Gieger, Christian
  • Gilhuijs-Pederson, Lisa A
  • Glessner, Joseph T
  • Goel, Anuj
  • Gong, Yan
  • Grant, Struan FA
  • Grobbee, Diederick E
  • Hastie, Claire
  • Humphries, Steve E
  • Kim, Cecilia E
  • Kivimaki, Mika
  • Kleber, Marcus
  • Meisinger, Christa
  • Kumari, Meena
  • Langaee, Taimour Y
  • Lawlor, Debbie A
  • Li, Mingyao
  • Lobmeyer, Maximilian T
  • Maitland-van der Zee, Anke-Hilse
  • Meijs, Matthijs FL
  • Molony, Cliona M
  • Morrow, David A
  • Murugesan, Gurunathan
  • Musani, Solomon K
  • Nelson, Christopher P
  • Newhouse, Stephen J
  • O'Connell, Jeffery R
  • Padmanabhan, Sandosh
  • Palmen, Jutta
  • Patel, Sanjey R
  • Pepine, Carl J
  • Pettinger, Mary
  • Price, Thomas S
  • Rafelt, Suzanne
  • Ranchalis, Jane
  • Rasheed, Asif
  • Rosenthal, Elisabeth
  • Ruczinski, Ingo
  • Shah, Sonia
  • Shen, Haiqing
  • Silbernagel, Günther
  • Smith, Erin N
  • Spijkerman, Annemieke WM
  • Stanton, Alice
  • Steffes, Michael W
  • Thorand, Barbara
  • Trip, Mieke
  • van der Harst, Pim
  • van der A, Daphne L
  • van Iperen, Erik PA
  • van Setten, Jessica
  • van Vliet-Ostaptchouk, Jana V
  • Verweij, Niek
  • Wolffenbuttel, Bruce HR
  • Young, Taylor
  • Zafarmand, M Hadi
  • Zmuda, Joseph M
  • Boehnke, Michael
  • Altshuler, David
  • McCarthy, Mark
  • Kao, WH Linda
  • Pankow, James S
  • Cappola, Thomas P
  • Sever, Peter
  • Poulter, Neil
  • Caulfield, Mark
  • Dominiczak, Anna
  • Shields, Denis C
  • Bhatt, Deepak L
  • Zhang, Li
  • Curtis, Sean P
  • Danesh, John
  • Casas, Juan P
  • van der Schouw, Yvonne T
  • Onland-Moret, N Charlotte
  • Doevendans, Pieter A
  • Dorn, Gerald W
  • Farrall, Martin
  • FitzGerald, Garret A
  • Hamsten, Anders
  • Hegele, Robert
  • Hingorani, Aroon D
  • Hofker, Marten H
  • Huggins, Gordon S
  • Illig, Thomas
  • Jarvik, Gail P
  • Johnson, Julie A
  • Klungel, Olaf H
  • Knowler, William C
  • Koenig, Wolfgang
  • März, Winfried
  • Meigs, James B
  • Melander, Olle
  • Munroe, Patricia B
  • Mitchell, Braxton D
  • Bielinski, Susan J
  • Rader, Daniel J
  • Reilly, Muredach P
  • Rich, Stephen S
  • Rotter, Jerome I
  • Saleheen, Danish
  • Samani, Nilesh J
  • Schadt, Eric E
  • Shuldiner, Alan R
  • Silverstein, Roy
  • Kottke-Marchant, Kandice
  • Talmud, Philippa J
  • Watkins, Hugh
  • Asselbergs, Folkert W
  • de Bakker, Paul IW
  • McCaffery, Jeanne
  • Wijmenga, Cisca
  • Sabatine, Marc S
  • Wilson, James G
  • Reiner, Alex
  • Bowden, Donald W
  • Hakonarson, Hakon
  • Siscovick, David S
  • Keating, Brendan J

publication date

  • March 2012

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