Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes

Maggie C. Y. Ng; Daniel Shriner; Brian H. Chen; Jiang Li; Wei-Min Chen; Xiuqing Guo; Jiankang Liu; Suzette J. Bielinski; Lisa R. Yanek; Michael A. Nalls; Mary E. Comeau; Laura J. Rasmussen-Torvik; Richard A. Jensen; Daniel S. Evans; Yan V. Sun; Ping An; Sanjay R. Patel; Yingchang Lu; Jirong Long; Loren L. Armstrong; Lynne Wagenknecht; Lingyao Yang; Beverly M. Snively; Nicholette D. Palmer; Poorva Mudgal; Carl D. Langefeld; Keith L. Keene; Barry I. Freedman; Josyf C. Mychaleckyj; Uma Nayak; Leslie J. Raffel; Mark O. Goodarzi; Y.-D. Ida Chen; Herman A. Taylor; Adolfo Correa; Mario Sims; David Couper; James S. Pankow; Eric Boerwinkle; Adebowale Adeyemo; Ayo Doumatey; Guanjie Chen; Rasika A. Mathias; Dhananjay Vaidya; Andrew B. Singleton; Alan B. Zonderman; Robert P. Igo; for the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium,; FIND Consortium; eMERGE Consortium; DIAGRAM Consortium; MuTHER Consortium

doi:10.1371/journal.pgen.1004517

Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes

Maggie C. Y. Ng (Lead / Corresponding author), Daniel Shriner (Lead / Corresponding author), Brian H. Chen, Jiang Li, Wei-Min Chen, Xiuqing Guo, Jiankang Liu, Suzette J. Bielinski, Lisa R. Yanek, Michael A. Nalls, Mary E. Comeau, Laura J. Rasmussen-Torvik, Richard A. Jensen, Daniel S. Evans, Yan V. Sun, Ping An, Sanjay R. Patel, Yingchang Lu, Jirong Long, Loren L. ArmstrongLynne Wagenknecht, Lingyao Yang, Beverly M. Snively, Nicholette D. Palmer, Poorva Mudgal, Carl D. Langefeld, Keith L. Keene, Barry I. Freedman, Josyf C. Mychaleckyj, Uma Nayak, Leslie J. Raffel, Mark O. Goodarzi, Y.-D. Ida Chen, Herman A. Taylor, Adolfo Correa, Mario Sims, David Couper, James S. Pankow, Eric Boerwinkle, Adebowale Adeyemo, Ayo Doumatey, Guanjie Chen, Rasika A. Mathias, Dhananjay Vaidya, Andrew B. Singleton, Alan B. Zonderman, Robert P. Igo, for the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium,, FIND Consortium, eMERGE Consortium, DIAGRAM Consortium, MuTHER Consortium

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Abstract

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 (4.15 × 10(-94)<P<5 × 10(-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 (2.2 × 10(-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.

Original language	English
Article number	e1004517
Pages (from-to)	1-14
Number of pages	14
Journal	PLoS Genetics
Volume	10
Issue number	8
DOIs	https://doi.org/10.1371/journal.pgen.1004517
Publication status	Published - 7 Aug 2014

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Ng, M. C. Y., Shriner, D., Chen, B. H., Li, J., Chen, W.-M., Guo, X., Liu, J., Bielinski, S. J., Yanek, L. R., Nalls, M. A., Comeau, M. E., Rasmussen-Torvik, L. J., Jensen, R. A., Evans, D. S., Sun, Y. V., An, P., Patel, S. R., Lu, Y., Long, J., ... MuTHER Consortium (2014). Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genetics, 10(8), 1-14. Article e1004517. https://doi.org/10.1371/journal.pgen.1004517

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title = "Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes",

abstract = "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 (4.15 × 10(-94)",

author = "Ng, {Maggie C. Y.} and Daniel Shriner and Chen, {Brian H.} and Jiang Li and Wei-Min Chen and Xiuqing Guo and Jiankang Liu and Bielinski, {Suzette J.} and Yanek, {Lisa R.} and Nalls, {Michael A.} and Comeau, {Mary E.} and Rasmussen-Torvik, {Laura J.} and Jensen, {Richard A.} and Evans, {Daniel S.} and Sun, {Yan V.} and Ping An and Patel, {Sanjay R.} and Yingchang Lu and Jirong Long and Armstrong, {Loren L.} and Lynne Wagenknecht and Lingyao Yang and Snively, {Beverly M.} and Palmer, {Nicholette D.} and Poorva Mudgal and Langefeld, {Carl D.} and Keene, {Keith L.} and Freedman, {Barry I.} and Mychaleckyj, {Josyf C.} and Uma Nayak and Raffel, {Leslie J.} and Goodarzi, {Mark O.} and Chen, {Y.-D. Ida} and Taylor, {Herman A.} and Adolfo Correa and Mario Sims and David Couper and Pankow, {James S.} and Eric Boerwinkle and Adebowale Adeyemo and Ayo Doumatey and Guanjie Chen and Mathias, {Rasika A.} and Dhananjay Vaidya and Singleton, {Andrew B.} and Zonderman, {Alan B.} and Igo, {Robert P.} and {for the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium,} and {FIND Consortium} and {eMERGE Consortium} and {DIAGRAM Consortium} and Doney, {Alex S. F.} and Morris, {Andrew D.} and Palmer, {Colin N. A.} and {MuTHER Consortium}",

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Ng, MCY, Shriner, D, Chen, BH, Li, J, Chen, W-M, Guo, X, Liu, J, Bielinski, SJ, Yanek, LR, Nalls, MA, Comeau, ME, Rasmussen-Torvik, LJ, Jensen, RA, Evans, DS, Sun, YV, An, P, Patel, SR, Lu, Y, Long, J, Armstrong, LL, Wagenknecht, L, Yang, L, Snively, BM, Palmer, ND, Mudgal, P, Langefeld, CD, Keene, KL, Freedman, BI, Mychaleckyj, JC, Nayak, U, Raffel, LJ, Goodarzi, MO, Chen, Y-DI, Taylor, HA, Correa, A, Sims, M, Couper, D, Pankow, JS, Boerwinkle, E, Adeyemo, A, Doumatey, A, Chen, G, Mathias, RA, Vaidya, D, Singleton, AB, Zonderman, AB, Igo, RP, for the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium, FIND Consortium, eMERGE Consortium, DIAGRAM Consortium & MuTHER Consortium 2014, 'Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes', PLoS Genetics, vol. 10, no. 8, e1004517, pp. 1-14. https://doi.org/10.1371/journal.pgen.1004517

Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. / Ng, Maggie C. Y. (Lead / Corresponding author); Shriner, Daniel (Lead / Corresponding author); Chen, Brian H. et al.
In: PLoS Genetics, Vol. 10, No. 8, e1004517, 07.08.2014, p. 1-14.

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

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AU - Ng, Maggie C. Y.

AU - Shriner, Daniel

AU - Chen, Brian H.

AU - Li, Jiang

AU - Chen, Wei-Min

AU - Guo, Xiuqing

AU - Liu, Jiankang

AU - Bielinski, Suzette J.

AU - Yanek, Lisa R.

AU - Nalls, Michael A.

AU - Comeau, Mary E.

AU - Rasmussen-Torvik, Laura J.

AU - Jensen, Richard A.

AU - Evans, Daniel S.

AU - Sun, Yan V.

AU - An, Ping

AU - Patel, Sanjay R.

AU - Lu, Yingchang

AU - Long, Jirong

AU - Armstrong, Loren L.

AU - Wagenknecht, Lynne

AU - Yang, Lingyao

AU - Snively, Beverly M.

AU - Palmer, Nicholette D.

AU - Mudgal, Poorva

AU - Langefeld, Carl D.

AU - Keene, Keith L.

AU - Freedman, Barry I.

AU - Mychaleckyj, Josyf C.

AU - Nayak, Uma

AU - Raffel, Leslie J.

AU - Goodarzi, Mark O.

AU - Chen, Y.-D. Ida

AU - Taylor, Herman A.

AU - Correa, Adolfo

AU - Sims, Mario

AU - Couper, David

AU - Pankow, James S.

AU - Boerwinkle, Eric

AU - Adeyemo, Adebowale

AU - Doumatey, Ayo

AU - Chen, Guanjie

AU - Mathias, Rasika A.

AU - Vaidya, Dhananjay

AU - Singleton, Andrew B.

AU - Zonderman, Alan B.

AU - Igo, Robert P.

AU - for the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium,

AU - FIND Consortium

AU - eMERGE Consortium

AU - DIAGRAM Consortium

AU - Doney, Alex S. F.

AU - Morris, Andrew D.

AU - Palmer, Colin N. A.

AU - MuTHER Consortium

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Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes

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