Open Access Open Badges Research article

Reproductive aging-associated common genetic variants and the risk of breast cancer

Chunyan He12*, Daniel I Chasman3, Jill Dreyfus4, Shih-Jen Hwang5, Rikje Ruiter6, Serena Sanna7, Julie E Buring3, Lindsay Fernández-Rhodes8, Nora Franceschini8, Susan E Hankinson109, Albert Hofman6, Kathryn L Lunetta115, Giuseppe Palmieri12, Eleonora Porcu7, Fernando Rivadeneira13146, Lynda M Rose3, Greta L Splansky5, Lisette Stolk1314, André G Uitterlinden13146, Stephen J Chanock15, Laura Crisponi7, Ellen W Demerath4, Joanne M Murabito165, Paul M Ridker3, Bruno H Stricker136 and David J Hunter10179

Author Affiliations

1 Department of Public Health, Indiana University School of Medicine, 980 West Walnut Street, R3-C241, Indianapolis, IN 46202, USA

2 Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, Indianapolis, IN 46202, USA

3 Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215, USA

4 Division of Epidemiology and Community Health, School of Public Health, 1300 South Second Street, Suite 300, University of Minnesota, Minneapolis, MN 55454, USA

5 Framingham Heart Study, The National Heart Lung and Blood Institute, 73 Mount Wayte, Suite 2, Framingham, MA 01701, USA

6 Department of Epidemiology, Erasmus Medical Center, 3015 GE, Rotterdam, The Netherlands

7 Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy

8 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 137 East Franklin Street, Suite 306, CB #8050, Chapel Hill, NC 27599, USA

9 Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA

10 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard medical School, 181 Longwood Avenue, Boston, MA 02115, USA

11 Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, 3rd floor, Boston, MA 02118, USA

12 Unit of Cancer Genetics, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Li Punti, 07100 Sassari, Italy

13 Department of Internal Medicine, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands

14 Netherlands Consortium of Healthy Aging, Rotterdam, Rotterdam, The Netherlands

15 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Bethesda, MD 20892, USA

16 Sections of General Internal Medicine, Department of Medicine, Boston University School of Medicine, 720 East Concord Street, Boston, MA 02118, USA

17 Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, 301 Binney Street, Cambridge, MA 02142, USA

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Breast Cancer Research 2012, 14:R54  doi:10.1186/bcr3155

Published: 20 March 2012



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.


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.


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.


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.