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.
| Original language | English |
|---|---|
| Pages (from-to) | 410-425 |
| Number of pages | 16 |
| Journal | American journal of human genetics |
| Volume | 90 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 9 2012 |
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Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. / Saxena, Richa; Elbers, Clara C.; Guo, Yiran; Peter, Inga; Gaunt, Tom R.; Mega, Jessica L.; Lanktree, Matthew B.; 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 C.H.; 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 F.A.; 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 F.L.; 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 W.M.; Stanton, Alice; Steffes, Michael W.; Thorand, Barbara; Trip, Mieke; Van Der Harst, Pim; Van Der A, Daphne L.; Van Iperen, Erik P.A.; Van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Wolffenbuttel, Bruce H.R.; Young, Taylor; Zafarmand, M. Hadi; Zmuda, Joseph M.; Boehnke, Michael; Altshuler, David; McCarthy, Mark; Kao, W. H.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 I.W.; McCaffery, Jeanne; Wijmenga, Cisca; Sabatine, Marc S.; Wilson, James G.; Reiner, Alex; Bowden, Donald W.; Hakonarson, Hakon; Siscovick, David S.; Keating, Brendan J.
In: American journal of human genetics, Vol. 90, No. 3, 09.03.2012, p. 410-425.Research output: Contribution to journal › Article › 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 - 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 - 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.
N1 - Funding Information: The CARe Consortium wishes to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard University and the Massachusetts Institute of Technology (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Cleveland Family Study (CFS), the Cooperative Study of Sickle Cell Disease (CSSCD), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). R.S. is partially supported by NIDDK NIH R21 (DK089378). C.C.E is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (NWO). Additional acknowledgements for each cohort are listed in the Supplemental Data. Also see the Supplemental Data for conflict-of-interest disclosures for some of the authors.
PY - 2012/3/9
Y1 - 2012/3/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862785585&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.12.022
DO - 10.1016/j.ajhg.2011.12.022
M3 - Article
C2 - 22325160
AN - SCOPUS:84862785585
VL - 90
SP - 410
EP - 425
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -