title: Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk.
abstract: 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.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA. egoode@mayo.edu
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Phelan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Anderson
authors.forename: David N
authors.initials: DN
authors.lastname: Rider
authors.forename: Kristin L
authors.initials: KL
authors.lastname: White
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Honglin
authors.initials: H
authors.lastname: Song
authors.forename: Estrid
authors.initials: E
authors.lastname: Hogdall
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.forename: Richard
authors.initials: R
authors.lastname: DiCioccio
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.forename: Paul P D
authors.initials: PP
authors.lastname: Pharaoh
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
mesh_terms: 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
chemical_list: 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