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：

美国国家卫生研究院; 美国医疗保健研究与质量局;

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

共 50 条

[21] Genome-wide association study provides insights into the genetic architecture of bone size and mass in chickens
Guo, Jun
Qu, Liang
Dou, Tao-Cun
Shen, Man-Man
Hu, Yu-Ping
Ma, Meng
Wang, Ke-Hua
GENOME, 2020, 63 (03) : 133 - 143
[22] Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes
Henry, Albert
Mo, Xiaodong
Finan, Chris
Chaffin, Mark D.
Speed, Doug
Issa, Hanane
Denaxas, Spiros
Ware, James S.
Zheng, Sean L.
Malarstig, Anders
Gratton, Jasmine
Bond, Isabelle
Roselli, Carolina
Miller, David
Chopade, Sandesh
Schmidt, A. Floriaan
Abner, Erik
Adams, Lance
Andersson, Charlotte
Aragam, Krishna G.
Arnlov, Johan
Asselin, Geraldine
Raja, Anna Axelsson
Backman, Joshua D.
Bartz, Traci M.
Biddinger, Kiran J.
Biggs, Mary L.
Bloom, Heather L.
Boersma, Eric
Brandimarto, Jeffrey
Brown, Michael R.
Brunak, Soren
Bruun, Mie Topholm
Buckbinder, Leonard
Bundgaard, Henning
Carey, David J.
Chasman, Daniel I.
Chen, Xing
Cook, James P.
Czuba, Tomasz
de Denus, Simon
Dehghan, Abbas
Delgado, Graciela E.
Doney, Alexander S.
Doerr, Marcus
Dowsett, Joseph
Dudley, Samuel C.
Engstrom, Gunnar
Erikstrup, Christian
Esko, Tonu
NATURE GENETICS, 2025, : 815 - 828
[23] Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes
Morris, Andrew P.
Voight, Benjamin F.
Teslovich, Tanya M.
Ferreira, Teresa
Segre, Ayellet V.
Steinthorsdottir, Valgerdur
Strawbridge, Rona J.
Khan, Hassan
Grallert, Harald
Mahajan, Anubha
Prokopenko, Inga
Kang, Hyun Min
Dina, Christian
Esko, Tonu
Fraser, Ross M.
Kanoni, Stavroula
Kumar, Ashish
Lagou, Vasiliki
Langenberg, Claudia
Luan, Jian'an
Lindgren, Cecilia M.
Mueller-Nurasyid, Martina
Pechlivanis, Sonali
Rayner, N. William
Scott, Laura J.
Wiltshire, Steven
Yengo, Loic
Kinnunen, Leena
Rossin, Elizabeth J.
Raychaudhuri, Soumya
Johnson, Andrew D.
Dimas, Antigone S.
Loos, Ruth J. F.
Vedantam, Sailaja
Chen, Han
Florez, Jose C.
Fox, Caroline
Liu, Ching-Ti
Rybin, Denis
Couper, David J.
Kao, Wen Hong L.
Li, Man
Cornelis, Marilyn C.
Kraft, Peter
Sun, Qi
van Dam, Rob M.
Stringham, Heather M.
Chines, Peter S.
Fischer, Krista
Fontanillas, Pierre
NATURE GENETICS, 2012, 44 (09) : 981 - +
[24] Meta-Analysis of Genome-wide Association Studies with Overlapping Subjects
Lin, Dan-Yu
Sullivan, Patrick F.
AMERICAN JOURNAL OF HUMAN GENETICS, 2009, 85 (06) : 862 - 872
[25] Optimal Methods for Meta-Analysis of Genome-Wide Association Studies
Zhou, Baiyu
Shi, Jianxin
Whittemore, Alice S.
GENETIC EPIDEMIOLOGY, 2011, 35 (07) : 581 - 591
[26] Shared genetic architecture of hernias: A genome-wide association study with multivariable meta-analysis of multiple hernia phenotypes
Ahmed, Waheed Ul-Rahman
Patel, Manal I. A.
Ng, Michael
McVeigh, James
Zondervan, Krina
Wiberg, Akira
Furniss, Dominic
PLOS ONE, 2022, 17 (12):
[27] Genome-Wide Association of BMI in African Americans
Ng, Maggie C. Y.
Hester, Jessica M.
Wing, Maria R.
Li, Jiang
Xu, Jianzhao
Hicks, Pamela J.
Roh, Bong H.
Lu, Lingyi
Divers, Jasmin
Langefeld, Carl D.
Freedman, Barry I.
Palmer, Nichole D.
Bowden, Donald W.
OBESITY, 2012, 20 (03) : 622 - 627
[28] GWAR: robust analysis and meta-analysis of genome-wide association studies
Dimou, Niki L.
Tsirigos, Konstantinos D.
Elofsson, Arne
Bagos, Pantelis G.
BIOINFORMATICS, 2017, 33 (10) : 1521 - 1527
[29] Meta-analysis of genome-wide association studies of HDL cholesterol response to statins
Postmus, Iris
Warren, Helen R.
Trompet, Stella
Arsenault, Benoit J.
Avery, Christy L.
Bis, Joshua C.
Chasman, Daniel I.
de Keyser, Catherine E.
Deshmukh, Harshal A.
Evans, Daniel S.
Feng, QiPing
Li, Xiaohui
Smit, Roelof A. J.
Smith, Albert V.
Sun, Fangui
Taylor, Kent D.
Arnold, Alice M.
Barnes, Michael R.
Barratt, Bryan J.
Betteridge, John
Boekholdt, S. Matthijs
Boerwinkle, Eric
Buckley, Brendan M.
Chen, Y-D Ida
de Craen, Anton J. M.
Cummings, Steven R.
Denny, Joshua C.
Dube, Marie Pierre
Durrington, Paul N.
Eiriksdottir, Gudny
Ford, Ian
Guo, Xiuqing
Harris, Tamara B.
Heckbert, Susan R.
Hofman, Albert
Hovingh, G. Kees
Kastelein, John J. P.
Launer, Leonore J.
Liu, Ching-Ti
Liu, Yongmei
Lumley, Thomas
McKeigue, Paul M.
Munroe, Patricia B.
Neil, Andrew
Nickerson, Deborah A.
Nyberg, Fredrik
O'Brien, Eoin
O'Donnell, Christopher J.
Post, Wendy
Poulter, Neil
JOURNAL OF MEDICAL GENETICS, 2016, 53 (12) : 835 - +
[30] Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis
Holliday, Elizabeth G.
Smith, Albert V.
Cornes, Belinda K.
Buitendijk, Gabrielle H. S.
Jensen, Richard A.
Sim, Xueling
Aspelund, Thor
Aung, Tin
Baird, Paul N.
Boerwinkle, Eric
Cheng, Ching Yu
van Duijn, Cornelia M.
Eiriksdottir, Gudny
Gudnason, Vilmundur
Harris, Tamara
Hewitt, Alex W.
Inouye, Michael
Jonasson, Fridbert
Klein, Barbara E. K.
Launer, Lenore
Li, Xiaohui
Liew, Gerald
Lumley, Thomas
McElduff, Patrick
McKnight, Barbara
Mitchell, Paul
Psaty, Bruce M.
Rochtchina, Elena
Rotter, Jerome I.
Scott, Rodney J.
Tay, Wanting
Taylor, Kent
Teo, Yik Ying
Uitterlinden, Andre G.
Viswanathan, Ananth
Xie, Sophia
Vingerling, Johannes R.
Klaver, Caroline C. W.
Tai, E. Shyong
Siscovick, David
Klein, Ronald
Cotch, Mary Frances
Wong, Tien Y.
Attia, John
Wang, Jie Jin
PLOS ONE, 2013, 8 (01):

← 1 2 3 4 5 →