Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits with 222 Candidate Genes
- Kyle J. Gaulton, BAS1,
- Cristen J. Willer, PhD2,
- Yun Li, MS2,
- Laura J. Scott, PhD2,
- Karen N. Conneely, PhD2,
- Anne U. Jackson, PhD2,
- William L. Duren, MS2,
- Peter S. Chines, MS3,
- Narisu Narisu, PhD3,
- Lori L. Bonnycastle, PhD3,
- Jingchun Luo, PhD4,
- Maurine Tong, BS3,
- Andrew G. Sprau, BS3,
- Elizabeth W. Pugh, PhD5,
- Kimberly F. Doheny, PhD5,
- Timo T. Valle, MD6,
- Gonçalo R. Abecasis, PhD2,
- Jaakko Tuomilehto, MD, PhD6,7,8,
- Richard N. Bergman, PhD9,
- Francis S. Collins, MD, PhD3,
- Michael Boehnke, PhD2 and
- Karen L. Mohlke, PhD (mohlke{at}med.unc.edu)1
- 1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
- 2Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
- 3Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD
- 4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
- 5Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore MD
- 6Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
- 7Department of Public Health, University of Helsinki, Helsinki, Finland
- 8South Ostrobothnia Central Hospital, Seinäjoki, Finland
- 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
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- Received December 11, 2007.
- Accepted July 21, 2008.
- Copyright © American Diabetes Association
