Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk.
Polymorphisms in genes critical to cell cycle control are outstanding candidates for association with ovarian cancer risk; numerous genes have been interrogated by multiple research groups using differing tagging single-nucleotide polymorphism (SNP) sets. To maximize information gleaned from existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2, CDK4, RB1, CDKN2D, and CCNE1) and one gene region (CDKN2A-CDKN2B). Because of the semi-overlapping nature of the 123 assayed tagging SNPs, we performed multiple imputation based on fastPHASE using data from White non-Hispanic study participants and participants in the international HapMap Consortium and National Institute of Environmental Health Sciences SNPs Program. Logistic regression assuming a log-additive model was done on combined and imputed data. We observed strengthened signals in imputation-based analyses at several SNPs, particularly CDKN2A-CDKN2B rs3731239; CCND1 rs602652, rs3212879, rs649392, and rs3212891; CDK2 rs2069391, rs2069414, and rs17528736; and CCNE1 rs3218036. These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls.
Goode
Ellen L
EL
Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA. egoode@mayo.edu
Fridley
Brooke L
BL
Vierkant
Robert A
RA
Cunningham
Julie M
JM
Phelan
Catherine M
CM
Anderson
Stephanie
S
Rider
David N
DN
White
Kristin L
KL
Pankratz
V Shane
VS
Song
Honglin
H
Hogdall
Estrid
E
Kjaer
Susanne K
SK
Whittemore
Alice S
AS
DiCioccio
Richard
R
Ramus
Susan J
SJ
Gayther
Simon A
SA
Schildkraut
Joellen M
JM
Pharaoh
Paul P D
PP
Sellers
Thomas A
TA
D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008390:Markov Chains; D008875:Middle Aged; D008910:Minnesota; D009361:Neoplasm Invasiveness; D009657:North Carolina; D015513:Oncogene Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012042:Registries; D012306:Risk
C530104:CCND1 protein, human; C475820:CCNE1 protein, human; C493966:CDKN2B protein, human; D019927:Cyclin E; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015513:Oncogene Proteins; D019938:Cyclin D1; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2