Menarche and menopause are two fundamental physiological events during a woman's life. The timing of these events has a profound and long-lasting impact on women's health later in life, including risk of breast cancer. More than a dozen genome-wide association studies (GWAS) have been conducted in searching for common genetic variants associated with the reproductive aging traits, including age at menarche (AM) and age at natural menopause (ANM). However, the identified common variants collectively explain only a minor proportion of the heritability. Much of the missing heritability may be attributable to rare and low-frequency variants. Because African American (AA) girls tend to have menarche at a younger age than European American (EA) girls, the ramification of which on breast cancer risk remains unclear. Moreover, a majority of the previous GWAS for reproductive aging was carried out in women of European ancestry, and AAs have been understudied. By leveraging the existing exome array genotype data from a total of 8,350 AA breast cancer cases and healthy controls in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, we propose to identify rare and low-frequency coding variants associated with reproductive aging. We propose two Specific Aims: 1). To evaluate rare and low-frequency coding variants in the regions identified by previous GWAS for AM and ANM; 2) To identify rare and low-frequency coding variants across the genome associated with reproductive aging phenotypes. To our knowledge, this will be the first study to examine rare and low-frequency variants for reproductive aging phenotypes in AA women. Leveraging the existing exome array data from the largest AA breast cancer study makes our study highly cost-efficient. We expect to identify novel rare and low-frequency variants with large effects, which are beyond the spectrum of previous GWAS signals. The findings may explain the missing heritability for those phenotypes. The significance of studying reproductive aging genetics is irrefutably evident in numerous GWAS's performed. Although the variants discovered may not have an immediate impact on the prevention or treatment of breast cancer, this line of research is an important integrative step in advancing our understanding of the biology of reproductive aging and a plethora of diseases and conditions related to it, such as obesity, adult statue, diabetes, and breast cancer, which may, in turn, identify novel targets for intervention and prevention.
Menarche and menopause are two fundamental physiological events in a woman's life, and both age at menarche and age at natural menopause have a high heritability, indicating strong genetic influences on the timing of the events. By leveraging the existing exome genotyping array data from 8,350 African American women from a large consortium, this R03 application will perform the first analysis of rare and low-frequency variants for reproductive aging phenotypes in an understudied population, which may advance our knowledge of the biology of reproductive aging and its implications in a plethora of related diseases, including cancer.
| Coignet, Marie V; Zirpoli, Gary Robert; Roberts, Michelle R et al. (2017) Genetic variations, reproductive aging, and breast cancer risk in African American and European American women: The Women's Circle of Health Study. PLoS One 12:e0187205 |
