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Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes.

  • Author(s): Gaulton, Kyle J;
  • Willer, Cristen J;
  • Li, Yun;
  • Scott, Laura J;
  • Conneely, Karen N;
  • Jackson, Anne U;
  • Duren, William L;
  • Chines, Peter S;
  • Narisu, Narisu;
  • Bonnycastle, Lori L;
  • Luo, Jingchun;
  • Tong, Maurine;
  • Sprau, Andrew G;
  • Pugh, Elizabeth W;
  • Doheny, Kimberly F;
  • Valle, Timo T;
  • Abecasis, Gonçalo R;
  • Tuomilehto, Jaakko;
  • Bergman, Richard N;
  • Collins, Francis S;
  • Boehnke, Michael;
  • Mohlke, Karen L
  • et al.

Published Web Location

https://doi.org/10.2337/db07-1731
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.

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