Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits With 222 Candidate Genes
- Kyle J. Gaulton1,
- Cristen J. Willer2,
- Yun Li2,
- Laura J. Scott2,
- Karen N. Conneely2,
- Anne U. Jackson2,
- William L. Duren2,
- Peter S. Chines3,
- Narisu Narisu3,
- Lori L. Bonnycastle3,
- Jingchun Luo4,
- Maurine Tong3,
- Andrew G. Sprau3,
- Elizabeth W. Pugh5,
- Kimberly F. Doheny5,
- Timo T. Valle6,
- Gonçalo R. Abecasis2,
- Jaakko Tuomilehto678,
- Richard N. Bergman9,
- Francis S. Collins3,
- Michael Boehnke2 and
- Karen L. Mohlke1
- 1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- 2Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
- 3Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland
- 4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- 5Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
- 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, California
- Corresponding author: Karen Mohlke, mohlke{at}med.unc.edu
Abstract
OBJECTIVE—Type 2 diabetes 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 type 2 diabetes.
RESEARCH DESIGN AND METHODS—In a case-control study of 1,161 type 2 diabetic subjects and 1,174 control Finns who are normal glucose tolerant, 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 type 2 diabetic case subjects and 1,259 control subjects who are normal glucose tolerant, also from Finland.
RESULTS—Using SNP- and gene-based analysis methods, we replicated previously reported SNP-type 2 diabetes associations in PPARG, KCNJ11, and SLC2A2; identified significant SNPs in genes with previously reported associations (ENPP1 [rs2021966, P = 0.00026] and NRF1 [rs1882095, P = 0.00096]); and implicated novel genes, including RAPGEF1 (rs4740283, P = 0.00013) and TP53 (rs1042522, Arg72Pro, P = 0.00086), in type 2 diabetes susceptibility.
CONCLUSIONS—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 type 2 diabetes pathogenesis. Analysis of additional samples will be necessary to determine their effect on susceptibility.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008.
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- Accepted July 21, 2008.
- Received December 11, 2007.
- DIABETES
