Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

被引：162

作者：

Ng, Maggie C. Y. ^{[1
,2
]}

Shriner, Daniel ^{[3
]}

Chen, Brian H. ^{[4
,5
]}

Li, Jiang ^{[2
]}

Chen, Wei-Min ^{[6
,7
]}

Guo, Xiuqing ^{[8
]}

Liu, Jiankang ^{[9
]}

Bielinski, Suzette J. ^{[10
]}

Yanek, Lisa R. ^{[11
]}

Nalls, Michael A. ^{[12
]}

Comeau, Mary E. ^{[13
,14
]}

Rasmussen-Torvik, Laura J. ^{[15
]}

Jensen, Richard A. ^{[16
,17
]}

Evans, Daniel S. ^{[18
]}

Sun, Yan V. ^{[19
]}

An, Ping

Patel, Sanjay R. ^{[21
]}

Lu, Yingchang ^{[22
,23
]}

Long, Jirong ^{[24
]}

Armstrong, Loren L. ^{[25
]}

Wagenknecht, Lynne ^{[26
]}

Yang, Lingyao ^{[14
]}

Snively, Beverly M. ^{[14
]}

Palmer, Nicholette D. ^{[1
,2
,27
]}

Mudgal, Poorva ^{[2
]}

Langefeld, Carl D. ^{[13
,14
]}

Keene, Keith L. ^{[28
]}

Freedman, Barry I. ^{[29
]}

Mychaleckyj, Josyf C. ^{[6
,7
]}

Nayak, Uma ^{[6
,7
]}

Raffel, Leslie J. ^{[30
]}

Goodarzi, Mark O. ^{[30
]}

Chen, Y-D Ida ^{[8
]}

Taylor, Herman A., Jr. ^{[31
,32
]}

Correa, Adolfo ^{[31
]}

Sims, Mario ^{[31
]}

Couper, David ^{[33
]}

Pankow, James S. ^{[34
]}

Boerwinkle, Eric ^{[35
]}

Adeyemo, Adebowale ^{[3
]}

Doumatey, Ayo ^{[3
]}

Chen, Guanjie ^{[3
]}

Mathias, Rasika A. ^{[11
,36
]}

Vaidya, Dhananjay ^{[11
,37
]}

Singleton, Andrew B. ^{[12
]}

Zonderman, Alan B. ^{[38
]}

Igo, Robert P., Jr. ^{[39
]}

Sedor, John R. ^{[40
,41
]}

Kabagambe, Edmond K. ^{[42
]}

Siscovick, David S. ^{[16
,17
,43
]}

机构：

[1] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA

[2] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA

[3] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA

[4] Univ Calif Los Angeles, Sch Publ Hlth, Program Genom & Nutr, Los Angeles, CA 90024 USA

[5] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Metab Dis Prevent, Los Angeles, CA 90024 USA

[6] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[7] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA

[8] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA

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

[10] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA

[11] Johns Hopkins Univ, Dept Med, GeneSTAR Res Program, Div Gen Internal Med,Sch Med, Baltimore, MD USA

[12] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[13] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Publ Hlth Genom, Winston Salem, NC USA

[14] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA

[15] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA

[16] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA USA

[17] Univ Washington, Dept Med, Seattle, WA USA

[18] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, Res Inst, San Francisco, CA USA

[19] Emory Univ, Dept Epidemiol & Biomed Informat, Atlanta, GA 30322 USA

[20] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA

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

[22] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA

[23] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY USA

[24] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA

[25] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA

[26] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA

[27] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA

[28] E Carolina Univ, Dept Biol, Ctr Hlth Dispar, Greenville, NC USA

[29] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA

[30] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA

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

[32] Jackson State Univ, Tougaloo Coll, Jackson, MS USA

[33] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA

[34] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[35] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[36] Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Dept Med, Baltimore, MD USA

[37] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[38] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA

[39] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[40] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA

[41] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA

[42] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, Nashville, TN USA

[43] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[44] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[45] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA

[46] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[47] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[48] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA

[49] Int Epidemiol Inst, Rockville, MD USA

[50] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA

来源：

PLOS GENETICS | 2014年 / 10卷 / 08期

基金：

美国医疗保健研究与质量局; 美国国家卫生研究院;

关键词：

SUSCEPTIBILITY; LOCI; CONFIRMATION; RISK; EXPRESSION; HAPLOTYPES; EFFICIENT; LINKAGE; PACKAGE; PROTEIN;

D O I：

10.1371/journal.pgen.1004517

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15x10(-94) < P < 5x10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2x10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

引用

页数：14

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