Genetics: Genetic variants associated with menopause timing identified

The identification of 290 genetic variants associated with age at menopause is reported in a large genome-wide association study published in Nature. The knowledge of the biological mechanisms that govern reproductive lifespan afforded by this study may inform future studies designed to identify new therapeutic approaches for infertility treatments and to prevent disease.

On average, most women will experience menopause between the ages of 50 and 52 years. As women approach the menopause, their natural fertility reduces and the risk of conditions such as bone fractures or type 2 diabetes increases. Our understanding of why this happens — and subsequently the development of treatments to preserve fertility — is still limited.

John Perry and colleagues analysed genetic data from 201,323 women of European ancestry in whom natural menopause occurred between the ages of 40 and 60 years. Examination of around 13.1 million genetic variants led to the identification of 290 determinants of ovarian ageing that were associated with delayed menopause. A wide range of DNA damage response genes were found to be associated with the age at natural menopause, operating throughout a woman’s lifespan to control ovarian function. Specific experimental manipulation of two of these genes — Chek1 and Chek2 — in mice was shown to affect fertility and reproductive lifespan. In humans, further genetic analyses suggested a causal relationship between delayed menopause and improved bone health, as well as a reduced likelihood of developing type 2 diabetes. However, delayed menopause was also associated with an increased risk of hormone-sensitive cancers.

Although many influencers of reproductive age span — including non-genetic factors — remain unknown, the authors hope that these findings will inform future experimental studies into novel treatments to enhance female reproductive function and preserve fertility.

doi: 10.1038/s41586-021-03779-7

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