Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits with 222 Candidate Genes

  1. Kyle J. Gaulton, BAS1,
  2. Cristen J. Willer, PhD2,
  3. Yun Li, MS2,
  4. Laura J. Scott, PhD2,
  5. Karen N. Conneely, PhD2,
  6. Anne U. Jackson, PhD2,
  7. William L. Duren, MS2,
  8. Peter S. Chines, MS3,
  9. Narisu Narisu, PhD3,
  10. Lori L. Bonnycastle, PhD3,
  11. Jingchun Luo, PhD4,
  12. Maurine Tong, BS3,
  13. Andrew G. Sprau, BS3,
  14. Elizabeth W. Pugh, PhD5,
  15. Kimberly F. Doheny, PhD5,
  16. Timo T. Valle, MD6,
  17. Gonçalo R. Abecasis, PhD2,
  18. Jaakko Tuomilehto, MD, PhD6,7,8,
  19. Richard N. Bergman, PhD9,
  20. Francis S. Collins, MD, PhD3,
  21. Michael Boehnke, PhD2 and
  22. Karen L. Mohlke, PhD (mohlke{at}med.unc.edu)1
  1. 1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
  2. 2Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
  3. 3Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD
  4. 4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
  5. 5Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore MD
  6. 6Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
  7. 7Department of Public Health, University of Helsinki, Helsinki, Finland
  8. 8South Ostrobothnia Central Hospital, Seinäjoki, Finland
  9. 9Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA

    Abstract

    Objective: Type 2 diabetes (T2D) is a common complex disorder with environmental and genetic components. We used a candidate gene-based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to T2D.

    Research Design and Method: In a case-control study of 1,161 T2D and 1,174 normal glucose tolerant (NGT) control Finns, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 T2D cases and 1,259 NGT controls, also from Finland.

    Results: Using SNP and gene-based analysis methods, we replicated previously reported SNP- T2D associations in PPARG, KCNJ11, and SLC2A2, identified significant SNPs in genes with previously reported associations, ENPP1 (rs2021966, p=.00026) and NRF1 (rs1882095, p=.00096), and implicated novel genes in T2D susceptibility including RAPGEF1 (rs4740283, p=.00013) and TP53 (rs1042522; Arg72Pro, p=.00086).

    Conclusion: Our study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to T2D pathogenesis; analysis of additional samples will be necessary to determine their effect on susceptibility.

    Footnotes

      • Received December 11, 2007.
      • Accepted July 21, 2008.

    This Article

    1. Published online before print August 4, 2008, doi: 10.2337/db07-1731
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