The onset and conclusion of the reproductive life period are central factors influencing women's health later in life. Age at menarche and menopausal age affect risk for adverse health outcomes including osteoporosis, cardiovascular disease, and breast cancer. Further scientific study is needed to elucidate the contribution of menopause and reproductive factors versus aging per se to health conditions common in women in later life. More than half the variation in age at menarche and menopause is attributable to genetic factors yet the genes regulating these traits remain largely unknown. Data from longitudinal studies, such as the Framingham Heart Study (FHS), provide a wealth of data across adulthood including reproductive factors, disease occurrence, and health behaviors in both women and men. The FHS is multigenerational and includes an extensive genetics database with extant genotyping from a 550K genome-wide scan obtained through the NHLBI's SNP Health Association Resource (SHARe) project. We postulate that novel genetic variants influencing the age of menarche and natural menopause can be identified using a dense genome-wide association study (GWAS). This proposal has the following specific aims:
Aim 1. To identify genetic variants that influence age at menarche and age at natural menopause through a GWAS using extant 550K genotyping data. To perform in silico replication of significant associations in independent samples.
Aim 2. To examine the associations between genetic variants identified in aim 1 and osteoporosis-related traits obtained using dual x-ray absorptiometry (DXA) and hand radiogrammetry, in women as well as in men.
Aim 3. To perform a phenome scan using the genotypes associated with reproductive aging to identify other associated phenotypes that may provide additional insights into underlying biological mechanisms mediating the associations in women. The phenome scan will also be performed in men to explore sex-specific associations. The use of the 550K genotyping will be resource effective and our work will be publicly available through the FHS SHARe Project located at the NCBI permitting investigators around the world to embark on this research. Insights from this project may lead to the discovery of genes related to female reproductive aging and associated health outcomes and in turn lead to innovative diagnostic and therapeutic interventions to improve the overall health of women and possibly of men.
This project may lead to the discovery of genes related to female reproductive aging (menarche and menopause) and in turn provide insights into the pathophysiologic mechanisms leading to important health conditions later in life in women. Knowledge gained may lead to innovative diagnostic and therapeutic interventions to improve the overall health of women and possibly of men.
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