title: Reproductive aging-associated common genetic variants and the risk of breast cancer.
abstract: BACKGROUND
  A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.
  
  
  METHODS
  In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.
  
  
  RESULTS
  After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.
  
  
  CONCLUSIONS
  Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.
authors.affiliation: Department of Public Health, Indiana University School of Medicine, 980 West Walnut Street, R3-C241, Indianapolis, IN 46202, USA. chunhe@iupui.edu
authors.forename: Chunyan
authors.initials: C
authors.lastname: He
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Jill
authors.initials: J
authors.lastname: Dreyfus
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Rikje
authors.initials: R
authors.lastname: Ruiter
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Julie E
authors.initials: JE
authors.lastname: Buring
authors.forename: Lindsay
authors.initials: L
authors.lastname: Fernández-Rhodes
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palmieri
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Rose
authors.forename: Greta L
authors.initials: GL
authors.lastname: Splansky
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Demerath
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
mesh_terms: D000293:Adolescent; D000328:Adult; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006801:Humans; D008572:Menarche / Q000235:genetics*; D008593:Menopause / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics