Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans

The Candidate Gene Association Resource Plus Study

  1. Donald W. Bowden1,2,5,23
  1. 1Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina
  2. 2Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina
  3. 3Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  4. 4Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts
  5. 5Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina
  6. 6Department of Preventive Medicine, Northwestern University, Chicago, Illinois
  7. 7Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
  8. 8Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington
  9. 9Division of Sleep Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  10. 10Center for Healthy Communities, University of South Alabama College of Medicine, Mobile, Alabama
  11. 11School of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
  12. 12Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California
  13. 13Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
  14. 14Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
  15. 15Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  16. 16Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
  17. 17Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  18. 18General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
  19. 19Department of Medicine, Harvard Medical School, Boston, Massachusetts
  20. 20Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington
  21. 21Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota
  22. 22Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
  23. 23Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
  24. 24Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
  1. Corresponding author: Maggie C.Y. Ng, mng{at}wakehealth.edu.

Abstract

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.

Footnotes

  • Received March 2, 2012.
  • Accepted August 21, 2012.

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  1. Diabetes vol. 62 no. 3 965-976
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