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

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 11; pp. 3136 - 3144
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.11.2008
• Subjects: Adult; Aged; Annotations; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diagnosis; Female; Finland; Gene Frequency; Genes; Genes, p53 - genetics; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetics; Genomes; Genotype; Genotypes; Glucose; Glucose Transporter Type 2 - genetics; Humans; Male; Middle Aged; Nuclear Respiratory Factor 1 - genetics; Ontology; Phosphoric Diester Hydrolases - genetics; Physiological aspects; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying - genetics; Pyrophosphatases - genetics; Quantitative Trait, Heritable; Research design; Risk factors; Type 2 diabetes; Finland; United States; United States > US
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db07-1731

Comprehensive Association Study of Type 2 Diabetes and Related Quantitative Traits With 222 Candidate Genes Kyle J. Gaulton 1 , Cristen J. Willer 2 , Yun Li 2 , Laura J. Scott 2 , Karen N. Conneely 2 , Anne U. Jackson 2 , William L. Duren 2 , Peter S. Chines 3 , Narisu Narisu 3 , Lori L. Bonnycastle 3 , Jingchun Luo 4 , Maurine Tong 3 , Andrew G. Sprau 3 , Elizabeth W. Pugh 5 , Kimberly F. Doheny 5 , Timo T. Valle 6 , Gonçalo R. Abecasis 2 , Jaakko Tuomilehto 6 7 8 , Richard N. Bergman 9 , Francis S. Collins 3 , Michael Boehnke 2 and Karen L. Mohlke 1 1 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 2 Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 3 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 5 Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 6 Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland 7 Department of Public Health, University of Helsinki, Helsinki, Finland 8 South Ostrobothnia Central Hospital, Seinäjoki, Finland 9 Department 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 Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 21, 2008. Received December 11, 2007. DIABETES