New genes linked to longer reproductive lifespan in women identified

Research, including Generation Scotland volunteer data, identifies nearly 300 variations in genes that can affect reproductive lifespan in women

The age at which women go through menopause is critical for fertility and impacts healthy ageing in women. However, this ageing process has been difficult for scientists to study and insights into the biology of it are limited.

Now, scientists have identified nearly 300 gene variations that influence reproductive lifespan in women. In addition, several key genes associated with these variants have been successfully altered to extend the reproductive lifespan of mice.

The findings, published today in Nature, greatly increase our knowledge of the reproductive ageing process. They also provide ways to improve the prediction of which women might reach menopause earlier than others.

While life expectancy has greatly increased over the past 150 years, the age most women go through natural menopause has remained relatively constant, at about 50 years old. Women are born with all the eggs they will ever carry, and these are gradually lost with age. Menopause occurs once most of the eggs have gone. However natural fertility lowers much earlier.

It is clear that repairing damaged DNA in eggs is very important for establishing the pool of eggs women are born with and also for how quickly they are lost throughout life. Improved understanding of the biological processes involved in reproductive ageing could lead to improvements in fertility treatment options.

The new discoveries were made possible through the study of volunteer data from hundreds of thousands of women from many studies; including Generation Scotland, UK Biobank and 23andMe. While the large majority of women studied have European ancestry, researchers also examined data on nearly 80,000 women of East Asian ancestry. They found broadly similar results. The researchers' findings identify new genetic variations linked to reproductive lifespan, increasing the known number from 56 to 290.

Delighted that Generation Scotland could contribute to this ground-breaking study. The future impact of these findings on both fertility and the consequences of menopause has been greatly advanced.

The genes identified by this work influence the age of natural menopause. They can also be used to help predict which women are at the highest risk of having menopause at a young age.

The team also examined the health impacts of having an earlier or later menopause. They used an approach that tests the effect of naturally-occurring genetic differences. They found that a genetically earlier menopause increases the risk of type 2 diabetes and is linked to poorer bone health and an increased risk of fractures. However, early menopause decreases the risk of some types of cancer, such as ovarian and breast cancer, that are known to be sensitive to sex hormones which are at higher levels while a woman is still menstruating.

This research is incredibly exciting. Although there’s still a long way to go, by combining genetic analysis in humans with studies in mice, plus examining when these genes are switched on in human eggs, we now know a lot more about human reproductive ageing. It also gives us insights into how to help avoid some health problems that are linked to the timing of menopause.

The research team discovered that many of the genes involved are linked to DNA repair processes. They also found that many of these genes are active before birth, when human egg stores are created, and also throughout life as well.

Key examples include CHEK1 and CHEK2, which regulate a wide variety of DNA repair processes. Knocking out a specific gene (CHEK2) so that it no longer functions, and over-expressing another (CHEK1) to increase its activity, led to an approximately 25 per cent longer reproductive lifespan in mice. Mouse reproduction differs from humans in many ways. For example, mice do not have menopause. However, the study also looked at women who naturally lack an active CHEK2 gene, and found they reach menopause on average 3.5 years later than women with a normally active gene.

We saw that two of the genes which produce proteins involved in repairing damaged DNA work in opposite ways with respect to reproduction in mice. Female mice with more of the CHEK1 protein are born with more eggs and they take longer to deplete naturally, so reproductive lifespan is extended. However, while the second gene, CHEK2, has a similar effect, allowing eggs to survive longer, but in this case the gene has been knocked out so that no protein is produced suggesting that CHEK2 activation may cause egg death in adult mice.

This research has been achieved by a global partnership involving academics from more than 180 institutions. The research was jointly led by the University of Exeter, the MRC Epidemiology Unit at the University of Cambridge, the Institute of Biotechnology and Biomedicine at the Universitat Autònoma de Barcelona and the DNRF Center for Chromosome Stability at the University of Copenhagen.

This paper was published in Nature and can be found in the link below:

Genetic insights into biological mechanisms governing human ovarian ageing