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

Wednesday,2015-03-04 13:54 America/Los_Angeles — zdrager
TitleMeta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.
Publication TypeJournal Article
Year of Publication2014
AuthorsC Y Ng, M, 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-DIda, 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, Sedor, JR, Kabagambe, EK, Siscovick, DS, McKnight, B, Rice, K, Liu, Y, Hsueh, W-C, Zhao, W, Bielak, LF, Kraja, A, Province, MA, Bottinger, EP, Gottesman, O, Cai, Q, Zheng, W, Blot, WJ, Lowe, WL, Pacheco, JA, Crawford, DC, Grundberg, E, Rich, SS, M Hayes, G, Shu, X-O, Loos, RJF, Borecki, IB, Peyser, PA, Cummings, SR, Psaty, BM, Fornage, M, Iyengar, SK, Evans, MK, Becker, DM, Kao, LWH, Wilson, JG, Rotter, JI, Sale, MM, Liu, S, Rotimi, CN, Bowden, DW
Corporate/Institutional AuthorsFIND Consortium, eMERGE Consortium, DIAGRAM Consortium, MuTHER Consortium,, MEta-analysis of type 2 DIabetes in African Americans Consortium
JournalPLoS Genet
Volume10
Issue8
Paginatione1004517
Date Published2014 Aug
ISSN1553-7404
KeywordsAfrican Americans, Diabetes Mellitus, Type 2, Genome-Wide Association Study, HLA-B27 Antigen, HMGA2 Protein, Humans, KCNQ1 Potassium Channel, Mutant Chimeric Proteins, Polymorphism, Single Nucleotide, Transcription Factor 7-Like 2 Protein
Abstract<p>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.</p>
DOI10.1371/journal.pgen.1004517
Alternate JournalPLoS Genet.
PubMed ID25102180
PubMed Central IDPMC4125087
Grant ListR01 DK078616 / DK / NIDDK NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
U01-HG-004610 / HG / NHGRI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
R01-HL-088215 / HL / NHLBI NIH HHS / United States
U01DK057303 / DK / NIDDK NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
32105-6 / / PHS HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
UL1RR033176 / RR / NCRR NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
Z01-AG000513 / AG / NIA NIH HHS / United States
M01-RR-01346 / RR / NCRR NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
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HL59684 / HL / NHLBI NIH HHS / United States
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S06GM008016-380111 / GM / NIGMS NIH HHS / United States
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UL1 TR000150 / TR / NCATS NIH HHS / United States
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G12 MD007597 / MD / NIMHD NIH HHS / United States
HHSC268200782096C / / PHS HHS / United States
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N01HC85080 / HC / NHLBI NIH HHS / United States
UL1-RR-025005 / RR / NCRR NIH HHS / United States
HL071025-01A1 / HL / NHLBI NIH HHS / United States
HHSN268201300048C / / PHS HHS / United States
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NHGRI T32-HG002536 / / PHS HHS / United States
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HL105756 / HL / NHLBI NIH HHS / United States
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