title: Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes.
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.
  
  
  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.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Gaulton
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Scott
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.forename: William L
authors.initials: WL
authors.lastname: Duren
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.forename: Lori L
authors.initials: LL
authors.lastname: Bonnycastle
authors.forename: Jingchun
authors.initials: J
authors.lastname: Luo
authors.forename: Maurine
authors.initials: M
authors.lastname: Tong
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sprau
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Pugh
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: Timo T
authors.initials: TT
authors.lastname: Valle
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005387:Finland; D005787:Gene Frequency; D016158:Genes, p53 / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D051273:Glucose Transporter Type 2 / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics; D019655:Quantitative Trait, Heritable; D000099161:Kcnj11 Channel
chemical_list: D051273:Glucose Transporter Type 2; D051266:Nuclear Respiratory Factor 1; D010727:Phosphoric Diester Hydrolases; D024661:Potassium Channels, Inwardly Rectifying; D011755:Pyrophosphatases; D000099161:Kcnj11 Channel; C495633:NRF1 protein, human; C495680:SLC2A2 protein, human; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1