Females are endowed with a predetermined pool of oocytes, established during fetal development. This finite ovarian reserve undergoes a gradual decline throughout life, culminating in menopause. The rate of follicular atresia, alongside the initial size of the ovarian reserve, are pivotal factors in determining the age at which menopause occurs. Emerging evidence suggests that the biological pathways governing ovarian aging may also play a critical role in predisposing individuals to an increased risk of oncogenesis.
Stasa Stankovic and her colleagues have made significant strides in uncovering the genetic underpinnings of ovarian aging, cancer risk, and mutation rates. Through their large-scale study of 106,973 women from the UK Biobank, they identified rare genetic variants that exert a profound influence on ovarian aging. These discoveries provide important insights into how such variants not only affect the timing of menopause but also contribute to an increased risk of cancer. Particularly, they found that genes like SAMHD1, ZNF518A, ETAA1, PNPLA8, and PALB2 are closely associated with both early menopause and higher cancer susceptibility. By linking these genetic pathways, the team offers a deeper understanding of the dual role these factors play in ovarian aging and oncogenesis, advancing the knowledge of reproductive biology and disease risk.
A pivotal finding of the study is the identification of deleterious variants in the SAMHD1 gene, which are associated with an extended reproductive lifespan, yet concurrently increase the risk of several cancers, including prostate cancer in men and breast cancer in women. This association underscores the critical role of DNA repair mechanisms in preserving ovarian function and mitigating cancer risk. Conversely, harmful variants in ZNF518A are linked to the onset of menopause up to 5.6 years earlier than the average. The age at natural menopause (ANM) serves as a focal point in this research, marking the conclusion of a woman’s reproductive capacity and being shaped by an interplay of genetic, environmental, and biological factors. Variations in ANM have far-reaching implications not only for reproductive health but also for broader disease risks, including type 2 diabetes, cancer, and bone-related conditions. Notably, ANM has been shown to correlate strongly with fertility, which typically begins to decline approximately a decade prior to menopause.
The study conducted an extensive analysis of 106,973 post-menopausal women from the UK Biobank using whole-exome sequencing (WES), identifying numerous rare genetic variants associated with early ANM in genes such as ZNF518A, SAMHD1, and BRCA2. The findings revealed that, in comparison to common variants, rare protein-coding variants had a more pronounced effect on ANM. In particular, certain genes were found to accelerate the onset of menopause by as much as 5.61 years. Specifically, women carrying high-confidence protein-truncating variants (HC-PTVs) in ZNF518A experienced menopause 5.61 years earlier, whereas those with deleterious mutations in SAMHD1 exhibited a delay in menopause by 1.35 years.
One of the study’s more intriguing discoveries was the observation that women genetically predisposed to early ovarian aging exhibited elevated rates of de novo mutations in their offspring. By analyzing data from over 8,809 European ancestry parent-offspring trios, the researchers found that women with a genetic predisposition for earlier menopause had a higher incidence of maternally derived de novo mutations in their children. While this effect was evident in the UK Biobank data, it was not replicated in a separate dataset from deCODE Genetics, indicating that further investigation is required to validate this finding.
In summary, the study broadens the understanding of ovarian aging by uncovering rare genetic variants with significant effects on the timing of menopause, particularly in genes linked to DNA damage repair and reproductive longevity. These findings not only enhance the potential for targeted fertility treatments but also suggest broader implications for disease risk, including cancer. However, further research is needed to validate these associations in more diverse populations and to explore the role of non-coding genetic variation. As we advance, this foundational work lays the groundwork for future genomic studies that will deepen our understanding of ovarian aging mechanisms and their impact on women’s health across generations.
Author: Muhammet Gürkan Korkmaz
Editor: Elif Duymaz
Reference: Stankovic, S., Shekari, S., Huang, Q. Q., Gardner, E. J., Ivarsdottir, E. V., Owens, N. D. L., Mavaddat, N., Azad, A., Hawkes, G., Kentistou, K. A., Beaumont, R. N., Day, F. R., Zhao, Y., Jonsson, H., Rafnar, T., Tragante, V., Sveinbjornsson, G., Oddsson, A., Styrkarsdottir, U., . . . Murray, A. (2024). Genetic links between ovarian ageing, cancer risk and de novo mutation rates. Nature. https://doi.org/10.1038/s41586-024-07931-x
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