PubMed 18678618

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

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

Journal, date & volume: Diabetes, 2008 Nov , 57, 3136-44

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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.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.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.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.