Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes.
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.
Gaulton
Kyle J
KJ
Department of Genetics, University of North Carolina at Chapel Hill, North Carolina, USA.
Willer
Cristen J
CJ
Li
Yun
Y
Scott
Laura J
LJ
Conneely
Karen N
KN
Jackson
Anne U
AU
Duren
William L
WL
Chines
Peter S
PS
Narisu
Narisu
N
Bonnycastle
Lori L
LL
Luo
Jingchun
J
Tong
Maurine
M
Sprau
Andrew G
AG
Pugh
Elizabeth W
EW
Doheny
Kimberly F
KF
Valle
Timo T
TT
Abecasis
Gonçalo R
GR
Tuomilehto
Jaakko
J
Bergman
Richard N
RN
Collins
Francis S
FS
Boehnke
Michael
M
Mohlke
Karen L
KL
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
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