Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans
The Candidate Gene Association Resource Plus Study
- Maggie C.Y. Ng1,2⇓,
- Richa Saxena3,4,
- Jiang Li2,
- Nicholette D. Palmer1,2,5,
- Latchezar Dimitrov1,
- Jianzhao Xu2,
- Laura J. Rasmussen-Torvik6,
- Joseph M. Zmuda7,
- David S. Siscovick8,
- Sanjay R. Patel9,
- Errol D. Crook10,
- Mario Sims11,
- Yii-Der I. Chen12,13,
- Alain G. Bertoni14,
- Mingyao Li15,
- Struan F.A. Grant16,
- Josée Dupuis17,
- James B. Meigs18,19,
- Bruce M. Psaty20,
- James S. Pankow21,
- Carl D. Langefeld22,
- Barry I. Freedman23,
- Jerome I. Rotter13,
- James G. Wilson24 and
- Donald W. Bowden1,2,5,23
- 1Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina
- 2Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina
- 3Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
- 4Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts
- 5Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina
- 6Department of Preventive Medicine, Northwestern University, Chicago, Illinois
- 7Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
- 8Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington
- 9Division of Sleep Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- 10Center for Healthy Communities, University of South Alabama College of Medicine, Mobile, Alabama
- 11School of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
- 12Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California
- 13Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
- 14Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
- 15Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- 16Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- 17Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
- 18General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
- 19Department of Medicine, Harvard Medical School, Boston, Massachusetts
- 20Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington
- 21Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota
- 22Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
- 23Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
- 24Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
- Corresponding author: Maggie C.Y. Ng, .
Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10−8). Locus-wide analysis demonstrated significant associations (Pemp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0266/-/DC1.
- Received March 2, 2012.
- Accepted August 21, 2012.
- © 2013 by the American Diabetes Association.
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