Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

被引：204

作者：

Saxena, Richa ^{[1
,2
,3
]}

Elbers, Clara C. ^{[4
,5
,6
]}

Guo, Yiran ^{[7
,8
]}

Peter, Inga ^{[9
]}

Gaunt, Tom R. ^{[10
]}

Mega, Jessica L. ^{[11
]}

Lanktree, Matthew B. ^{[12
]}

Tare, Archana ^{[1
,2
]}

Almoguera Castillo, Berta ^{[7
,13
]}

Li, Yun R. ^{[7
]}

Johnson, Toby ^{[14
,15
]}

Bruinenberg, Marcel ^{[16
]}

Gilbert-Diamond, Diane ^{[17
,18
]}

Rajagopalan, Ramakrishnan ^{[19
]}

Voight, Benjamin F. ^{[1
,2
]}

Balasubramanyam, Ashok ^{[20
]}

Barnard, John ^{[21
]}

Bauer, Florianne ^{[5
,6
]}

Baumert, Jens ^{[22
]}

Bhangale, Tushar ^{[23
]}

Boehm, Bernhard O. ^{[24
]}

Braund, Peter S. ^{[25
]}

Burton, Paul R. ^{[26
]}

Chandrupatla, Hareesh R. ^{[27
]}

Clarke, Robert ^{[28
]}

Cooper-DeHoff, Rhonda M. ^{[29
,30
]}

Crook, Errol D. ^{[31
]}

Davey-Smith, George ^{[10
]}

Day, Ian N. ^{[10
]}

de Boer, Anthonius ^{[32
]}

de Groot, Mark C. H. ^{[32
]}

Drenos, Fotios ^{[33
]}

Ferguson, Jane ^{[27
]}

Fox, Caroline S. ^{[34
]}

Furlong, Clement E. ^{[19
,23
]}

Gibson, Quince ^{[35
]}

Gieger, Christian ^{[36
]}

Gilhuijs-Pederson, Lisa A. ^{[32
]}

Glessner, Joseph T. ^{[7
]}

Goel, Anuj ^{[37
]}

Gong, Yan ^{[30
]}

Grant, Struan F. A. ^{[7
]}

Grobbee, Diederick E. ^{[6
]}

Hastie, Claire ^{[38
]}

Humphries, Steve E. ^{[33
]}

Kim, Cecilia E. ^{[7
]}

Kivimaki, Mika ^{[39
,40
]}

Kleber, Marcus ^{[41
,42
]}

Meisinger, Christa ^{[22
]}

Kumari, Meena ^{[40
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[2] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[3] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA

[4] Univ Penn, Dept Genet, Sch Med, Philadelphia, PA 19104 USA

[5] Univ Med Ctr Utrecht, Complex Genet Sect, Dept Med Genet, Utrecht, Netherlands

[6] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[7] Childrens Hosp, Ctr Appl Genom, Abramson Res Ctr, Philadelphia, PA 19104 USA

[8] BGI Shenzhen, Shenzhen 518083, Peoples R China

[9] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA

[10] Univ Bristol, Med Res Council Ctr Causal Anal Translat Epidemio, Dept Social Med, Bristol BS8 2BN, Avon, England

[11] Brigham & Womens Hosp, Div Cardiovasc, Thrombolysis Myocardial Infarct Study Grp, Boston, MA 02115 USA

[12] Univ Western Ontario, Dept Biochem, London, ON N6A 5C1, Canada

[13] Fdn Jimenez Diaz, Serv Genet, Inst Invest Sanitaria, Madrid 228040, Spain

[14] Queen Mary Univ London, Barts & London Genome Ctr, London EC1M 6BQ, England

[15] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med, London EC1M 6BQ, England

[16] Univ Groningen, LifeLines Cohort Study & Biobank, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands

[17] Childrens Environm Hlth & Dis Prevent Ctr Dartmou, Hanover, NH 03755 USA

[18] Dartmouth Med Sch, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH 03756 USA

[19] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA

[20] Baylor Coll Med, Translat Metab Unit, Div Diabet Endocrinol & Metab, Houston, TX 77030 USA

[21] Cleveland Clin, Dept Quantitat Hlth Sci, Lerner Res Inst, Cleveland, OH 44195 USA

[22] German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany

[23] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[24] Cardiol Grp Frankfurt Sachsenhausen, D-60598 Frankfurt, Germany

[25] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Leicester LE3 9QP, Leics, England

[26] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England

[27] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[28] Clin Trial Serv Unit, Oxford OX3 7LF, England

[29] Univ Florida, Dept Pharmacotherapy & Translat Res, Coll Pharm, Gainesville, FL 32610 USA

[30] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32610 USA

[31] Univ S Alabama, Mobile, AL 36608 USA

[32] Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht Inst Pharmaceut Sci, Fac Sci, Utrecht, Netherlands

[33] UCL, Ctr Cardiovasc Genet, Dept Med, London WC1E 6JF, England

[34] Boston Univ, Sch Med, Boston, MA 02118 USA

[35] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[36] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[37] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[38] Univ Glasgow, British Heart Fdn Glasgow, Cardiovasc Res Ctr, Div Cardiovasc & Med Sci,Western Infirm, Glasgow G12 8TA, Lanark, Scotland

[39] UCL, Dept Epidemiol & Publ Hlth, London, England

[40] UCL, Genet Epidemiol Grp, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England

[41] LURIC Study, D-79098 Freiburg, Germany

[42] Synlab Ctr Lab Diagnost Heidelberg, D-69037 Heidelberg, Germany

[43] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands

[44] Rosetta Inpharmat, Dept Genet, Seattle, WA 98109 USA

[45] Cleveland Clin, Dept Clin Pathol, Pathol & Lab Med Inst, Cleveland, OH 44106 USA

[46] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA

[47] Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA

[48] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA

[49] Kings Coll London, Med Res Council, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England

[50] Ctr Noncommunicable Dis, Karachi, Pakistan

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2012年 / 90卷 / 03期

关键词：

GENOME-WIDE ASSOCIATION; INSULIN-RESISTANCE; COMMON VARIANTS; SUSCEPTIBILITY LOCI; EUROPEAN AMERICANS; AFRICAN-AMERICANS; BLOOD-PRESSURE; RISK LOCI; SNP ARRAY; POPULATION;

D O I：

10.1016/j.ajhg.2011.12.022

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：410 / 425

页数：16

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