Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci
Saxena R., Elbers CC., Guo Y., Peter I., Gaunt TR., Mega JL., Lanktree MB., Tare A., Castillo BA., Li YR., Johnson T., Bruinenberg M., Gilbert-Diamond D., Rajagopalan R., Voight BF., Balasubramanyam A., Barnard J., Bauer F., Baumert J., Bhangale T., Böhm BO., Braund PS., Burton PR., Chandrupatla HR., Clarke R., Cooper-Dehoff RM., Crook ED., Davey-Smith G., Day IN., De Boer A., De Groot MCH., Drenos F., Ferguson J., Fox CS., Furlong CE., Gibson Q., Gieger C., Gilhuijs-Pederson LA., Glessner JT., Goel A., Gong Y., Grant SFA., Grobbee DE., Hastie C., Humphries SE., Kim CE., Kivimaki M., Kleber M., Meisinger C., Kumari M., Langaee TY., Lawlor DA., Li M., Lobmeyer MT., Maitland-Van Der Zee AH., Meijs MFL., Molony CM., Morrow DA., Murugesan G., Musani SK., Nelson CP., Newhouse SJ., O'Connell JR., Padmanabhan S., Palmen J., Patel SR., Pepine CJ., Pettinger M., Price TS., Rafelt S., Ranchalis J., Rasheed A., Rosenthal E., Ruczinski I., Shah S., Shen H., Silbernagel G., Smith EN., Spijkerman AWM., Stanton A., Steffes MW., Thorand B., Trip M., Van Der Harst P.
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. © 2012 The American Society of Human Genetics.