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The role of genetics in women’s reproductive lifespan uncovered - and health impact of earlier menopause revealed

Nearly 300 gene variations that influence the reproductive lifespan of women have been identified by scientists in a global research collaboration.

Academics from more than 180 institutions, jointly led by the MRC Epidemiology Unit at the University of Cambridge, also successfully manipulated several key genes associated with the variants to extend their reproductive lifespan.

Genetic variations that a play a role in the menopause have been studied
Genetic variations that a play a role in the menopause have been studied

The research greatly increases our knowledge of the reproductive ageing process, could improve the prediction of which women might reach menopause earlier than others and lead to improvements in fertility treatment.

Women are born with all the eggs they will ever have. Menopause occurs at about 50 years old, when most of a woman’s eggs have gone, although natural fertility wanes years earlier.

Co-author Professor Eva Hoffmann, of the University of Copenhagen, said: “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 study increased our knowledge of known genetic variations linked to reproductive lifespan, from 56 to 290.

Testing the effect of naturally-occurring genetic differences also enabled the researchers to examine the health impacts of having an earlier or later menopause. A genetically earlier menopause was found to increase the risk of type 2 diabetes and was linked to poorer bone health and increased risk of fractures.

However, it reduced the risk of some types of cancer, such as ovarian and breast cancer, which are sensitive to sex hormones that are at higher levels while a woman is still menstruating.

The findings followed analyses of datasets from hundreds of thousands of women from sources including UK Biobank and 23andMe. Customers of 23andMe provided their data by opting in to the research.

Most of the data came from European women, but 80,000 of East Asian ancestry were included in the study, with broadly similar results.

They found many of the genes involved are linked to DNA repair processes. Many of these genes are active from before birth when human egg stores are created but also throughout life as well.

Two important cell cycle checkpoint pathways – CHEK1 and CHEK2 - regulate a wide variety of DNA repair processes.

The research showed knocking out the CHEK2 gene so that it no longer functions, and over-expressing CHEK1 to enhance its activity each led to an approximately 25 per cent longer reproductive lifespan in mice.

While mouse reproductive physiology differs from humans - notably mice do not have menopause - the study also looked at women who naturally lack an active CHEK2 gene, and found they typically reach menopause 3.5 years later than women with a normally active gene.

Co-author Professor Ignasi Roig, from the Universitat Autònoma de Barcelona, said: “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”.

The genes could be used to help predict which women are at highest risk of having menopause at a young age.

Co-author Dr Katherine Ruth, of the University of Exeter, said: “We hope our work will help provide new possibilities to help women plan for the future. By finding many more of the genetic causes of variability in the timing of menopause, we have shown that we can start to predict which women might have earlier menopause and therefore struggle to get pregnant naturally. And because we are born with our genetic variations, we could offer this advice to young women.”

Co-author Dr John Perry, of the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, a senior author on the paper, said: “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 collaboration involved was jointly led by the University of Exeter and the Cambridge’s MRC Epidemiology Unit, with the Institute of Biotechnology and Biomedicine at the Universitat Autònoma de Barcelona and the DNRF Center for Chromosome Stability at the University of Copenhagen.

The findings were published in Nature.

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