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

The MAGIC investigators, The GIANT consortium

Research output: Contribution to journalArticle

97 Citations (Scopus)

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 languageEnglish (US)
Article numbere1004517
JournalPLoS Genetics
Volume10
Issue number8
DOIs
StatePublished - Aug 7 2014

Fingerprint

diabetes
African American
Genome-Wide Association Study
meta-analysis
African Americans
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
Meta-Analysis
genome
loci
ancestry
single nucleotide polymorphism
Single Nucleotide Polymorphism
polymorphism
genome-wide association study
HLA-B Antigens
Linkage Disequilibrium
homeostasis
relative risk
liability

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes. / The MAGIC investigators; The GIANT consortium.

In: PLoS Genetics, Vol. 10, No. 8, e1004517, 07.08.2014.

Research output: Contribution to journalArticle

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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.",
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AU - The MAGIC investigators

AU - The GIANT consortium

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 - Sedor, John R.

AU - Zondervan, Krina T.

AU - Seldin, Michael F

PY - 2014/8/7

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AB - 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.

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