The Genetics of Female Reproductive Aging

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DESCRIPTION (provided by applicant): Aging of the reproductive system is unique in that human females reach a reproductively nonfunctional state at a time when they are otherwise healthy. Age at menopause is an inherited trait, and the ages at earlier reproductive stages (subfertility, infertility, and perimenopause) are strongly correlated with age at menopause. The age at naturally-occurring menopause is largely determined by the size of the initial primordial follicle pool and the rate of follicular atresia. Many biological factors are known to play a role in determining the size and quality of the follicle pool and the rate of decline of the ovarian reserve, and hence age at menopause. However, these factors interact through complex pathways, and very little is currently understood about the underlying genes and genetic variants that control these factors. We plan to identify genes that contribute to the control of female reproductive aging (see PA-06-347 Reproductive Genetics and Epigenetics). The long-term goals of our research are to: a) ascertain a very large population-based sample suitable for association studies of the quantitative trait ovarian reserve; b) screen a set of likely candidate genes for association with this trait; c) conduct high-density genome-wide association analysis; d) search for causative mutations in any genes with which association is detected. The short-term goals of this R03 Small Research Grant application are to begin the process of sample ascertainment and to begin screening candidate genes for association. For the pilot phase of this project we will enroll at least 150 subjects, and to improve power for future analyses, we plan to also enroll immediate family members. We will genotype single nucleotide polymorphisms (SNPs) from 9-10 candidate genes including AMH [anti-M¿llerian hormone], INHa, INH¿A, INH¿B, FOXL2, GDF9, BMP15, FOXO3A, and POF1B. SNPs from these genes will then be evaluated for association with biomarkers for ovarian reserve. The association testing will be based on Zhang's semiparametric test for association (SPTA) which uses a sample of 100-200 neutral markers to control for population stratification. Improved understanding of the role of genes in controlling female reproductive aging will increase our general knowledge of a critical physiological system and may shed light on general mechanisms of aging. We anticipate it will lead to the ability to predict at an early age whether a woman's ovarian reserve will decline faster or slower than average and whether she should anticipate early menopause. This will facilitate better family planning, which could reduce the need for age-related infertility treatment and reduce the incidence of miscarriage and aneuploidy among older mothers. Individualized evaluation of rate of reproductive aging will also be of considerable interest to female cancer patients, since cancer treatments often lead to reduction of ovarian reserve. Finally, enhancing our understanding of reproductive senescence may facilitate improvements in technologies used for assisted reproduction.