Endocrine Abstracts

Menopause timing is highly variable, having a direct effect on reproductive lifespan, fertility and health outcomes in later life. Endocrine and imaging tests only record changes in ovarian function that have already taken place, thus disabling early prediction and identification of women with reduced reproductive lifespan. Human genetic studies have attempted to overcome this problem by identifying genetic markers associated with menopause timing and fertility. Using data from large scale population studies, such as UK Biobank, we assessed both common and rare genetic variation that influence menopause timing. Our work on common genetic variants led to the discovery of 300 genetic signals that influence age women begin menopause and the first evidence of our ability to, through gene manipulation in a mouse model, extend reproductive lifespan by 25% and improve fertility. To assess the impact of rare damaging variants on menopause timing, we queried whole-exome sequencing data for 106,973 post-menopausal women in UK Biobank and implicated novel genes with effect sizes up to 6 times larger than previously discovered. Finally, we found that genetic susceptibility to earlier ovarian ageing in women increases de novo mutation rate in their offspring. This provides direct evidence that female mutation rate is heritable and highlights a mechanism of the maternal genome influencing child health, which could have direct implications for the health of future generations given the link between de novo mutations and disease risk. The power of this information is that in the future we may be able to build the first genetic prediction test that will inform women about the timing of her menopause. In addition, knowledge of underlying mechanisms may also allow their manipulation, more specifically halting or temporising the process of the loss of ovarian follicles and provide a new direction for therapeutic approaches that might seek to treat infertility.