Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

Richa Saxena; Clara C Elbers; Yiran Guo; Inga Peter; Tom R Gaunt; Jessica L Mega; Matthew B Lanktree; Archana Tare; Berta Almoguera Castillo; Yun R Li; Toby Johnson; Marcel Bruinenberg; Diane Gilbert-Diamond; Ramakrishnan Rajagopalan; Benjamin F Voight; Ashok Balasubramanyam; John Barnard; Florianne Bauer; Jens Baumert; Tushar Bhangale; Bernhard O Böhm; Peter S Braund; Paul R Burton; Hareesh R Chandrupatla; Robert Clarke; Rhonda M Cooper-DeHoff; Errol D Crook; George Davey-Smith; Ian N Day; Anthonius de Boer; Mark C H de Groot; Fotios Drenos; Jane Ferguson; Caroline S Fox; Clement E Furlong; Quince Gibson; Christian Gieger; Lisa A Gilhuijs-Pederson; Joseph T Glessner; Anuj Goel; Yan Gong; Struan F A Grant; Diederick E Grobbee; Claire Hastie; Steve E Humphries; Stephen J Newhouse; Thomas S Price; Erin N Smith; Li Zhang; James G Wilson; Look AHEAD Research Group

doi:10.1016/j.ajhg.2011.12.022

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

Richa Saxena, Clara C Elbers, Yiran Guo, Inga Peter, Tom R Gaunt, Jessica L Mega, Matthew B Lanktree, Archana Tare, Berta Almoguera Castillo, Yun R Li, Toby Johnson, Marcel Bruinenberg, Diane Gilbert-Diamond, Ramakrishnan Rajagopalan, Benjamin F Voight, Ashok Balasubramanyam, John Barnard, Florianne Bauer, Jens Baumert, Tushar BhangaleBernhard O Böhm, Peter S Braund, Paul R Burton, Hareesh R Chandrupatla, Robert Clarke, Rhonda M Cooper-DeHoff, Errol D Crook, George Davey-Smith, Ian N Day, Anthonius de Boer, Mark C H de Groot, Fotios Drenos, Jane Ferguson, Caroline S Fox, Clement E Furlong, Quince Gibson, Christian Gieger, Lisa A Gilhuijs-Pederson, Joseph T Glessner, Anuj Goel, Yan Gong, Struan F A Grant, Diederick E Grobbee, Claire Hastie, Steve E Humphries, Stephen J Newhouse, Thomas S Price, Erin N Smith, Li Zhang, James G Wilson, Look AHEAD Research Group

Research output: Contribution to journal › Article › peer-review

228 Citations (Scopus)

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)	410-25
Number of pages	16
Journal	American Journal of Human Genetics
Volume	90
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2011.12.022
Publication status	Published - Mar 2012

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2011.12.022

Cite this

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., ... Look AHEAD Research Group (2012). Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. American Journal of Human Genetics, 90(3), 410-25. https://doi.org/10.1016/j.ajhg.2011.12.022

@article{e4561418e45640ccb779cfd27ed0e2bb,

title = "Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci",

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.",

author = "Richa Saxena and Elbers, {Clara C} and Yiran Guo and Inga Peter and Gaunt, {Tom R} and Mega, {Jessica L} and Lanktree, {Matthew B} and Archana Tare and Castillo, {Berta Almoguera} and Li, {Yun R} and Toby Johnson and Marcel Bruinenberg and Diane Gilbert-Diamond and Ramakrishnan Rajagopalan and Voight, {Benjamin F} and Ashok Balasubramanyam and John Barnard and Florianne Bauer and Jens Baumert and Tushar Bhangale and B{\"o}hm, {Bernhard O} and Braund, {Peter S} and Burton, {Paul R} and Chandrupatla, {Hareesh R} and Robert Clarke and Cooper-DeHoff, {Rhonda M} and Crook, {Errol D} and George Davey-Smith and Day, {Ian N} and {de Boer}, Anthonius and {de Groot}, {Mark C H} and Fotios Drenos and Jane Ferguson and Fox, {Caroline S} and Furlong, {Clement E} and Quince Gibson and Christian Gieger and Gilhuijs-Pederson, {Lisa A} and Glessner, {Joseph T} and Anuj Goel and Yan Gong and Grant, {Struan F A} and Grobbee, {Diederick E} and Claire Hastie and Humphries, {Steve E} and Newhouse, {Stephen J} and Price, {Thomas S} and Smith, {Erin N} and Li Zhang and Wilson, {James G} and {Look AHEAD Research Group}",

year = "2012",

month = mar,

doi = "10.1016/j.ajhg.2011.12.022",

language = "English",

volume = "90",

pages = "410--25",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Elsevier",

number = "3",

}

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, Newhouse, SJ , Price, TS , Smith, EN , Zhang, L , Wilson, JG & Look AHEAD Research Group 2012, 'Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci', American Journal of Human Genetics, vol. 90, no. 3, pp. 410-25. https://doi.org/10.1016/j.ajhg.2011.12.022

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 - Newhouse, Stephen J

AU - Price, Thomas S

AU - Smith, Erin N

AU - Zhang, Li

AU - Wilson, James G

AU - Look AHEAD Research Group

PY - 2012/3

Y1 - 2012/3

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.

U2 - 10.1016/j.ajhg.2011.12.022

DO - 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 -

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this