A genome-wide association study (GWAS) has identified 290 genetic variants, including a wide range of DNA damage response (DDR) genes, that are associated with age at menopause.
Mouse models manipulating two of these DDR genes, the checkpoint kinases Chek1 and Chek2, showed they both had an effect on fertility and reproductive lifespan.
The study also provided new insights into how reproductive longevity influences healthy aging, suggesting for the first time that there is a causal relationship between later menopause and a reduced likelihood of developing type 2 diabetes.
Later menopause also was associated with improved bone health, but on the other hand was found to increase the risk of hormone-sensitive cancers.
Some of the genetic variants were shown to exert their effects over a few weeks, others over years, said Anna Murray, associate professor of human genetics at the University of Exeter, coauthor of a paper appearing in the August 5, 2021, issue of Nature.
Being fixed from birth, the variants could provide the basis of a polygenic predictor of the risk of early menopause. With fertility in decline for up to 10 years before menopause, this could help in family planning and avoid the need for fertility treatments, according to coauthor, Katherine Ruth, research fellow and specialist in female reproductive aging at the University of Exeter.
"We have shown that we can start to predict which women might have earlier menopause," said Ruth. The combined score from the 260 variants "couldn't identify all early menopauses, but it did a fairly good job. We are now working on an extension to the work, to improve prediction," she said.
Genetic factors are thought to account for about 50% of variation in menopause timing. Average age of menopause is between 47-52 years of age globally and early menopause, defined as happening before the age of 45, occurs in 4% of women.
The analysis involved genetic data from 201,323 women of European ancestry in whom natural menopause occurred between the ages of 40 and 60. More than 180 academic institutions were involved in the research, which has increased the number of known genetic variants linked to reproductive lifespan from 56 to 290.
John Perry, senior author and program leader at the MRC Epidemiology unit at Cambridge University, said ultimately it should be possible to make a precise prediction of age at menopause.
"We've already started on the genetic data of many more women, so we can assemble a larger dataset. It's also important to include women from different ethnicities," Perry said. "[We] want to get to a clinically relevant level; we want to get to the point where we can predict risk of early menopause."
Finding so many of the genes that play a role in reproductive aging are involved in DNA repair processes that are active from before birth, when egg stores are being created, provides pointers to improving success rates in in vitro fertilization (IVF). Modulating pathways involved in DNA damage repair in oocytes could make it possible to harvest more eggs.
Notable examples of DDR genes identified in the study are Chek1 and Chek2, which are involved in cell cycle checkpoint pathways. Chek1 helps DNA repair, whereas Chek2 plays a part in destroying eggs compromised by DNA damage, through apoptosis.
Introducing an extra copy of the Chek1 gene resulted in an increased ovarian reserve and a 25% longer reproductive lifespan in mice. Pups with an extra copy of Chek1 were born with a larger number of oocytes.
"We think that was a result of greater DNA repair," said co-author Eva Hoffman, professor of functional genomics and reproductive health at the University of Copenhagen, Denmark.
Meanwhile, the ovaries in Chek2 mice knockouts degenerated at a reduced rate compared to controls. Mice do not undergo menopause, but in animals of equivalent age to human menopause age, there was increased ovarian response to hormonal stimulation compared to control mice.
Fertilization rates in Chek2 knockouts were unaffected, as were embryonic development and litter size.
"Ablating Chek2, we found female mice without this [gene] had a slow decline of oocytes, probably because of less programmed cell death," Hoffman said.
Looking at women who have a loss of function mutation in the Chek2 gene, the researchers found they reached menopause on average 3.5 years later than women with a normally active gene.
"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," said Hoffman. "Improved understanding of the biological processes involved in reproductive aging could lead to improvements in fertility treatment options," she said.
Translational studies take time, but Hoffman noted, "Many of the genes identified are important in cancer and there are inhibitors to some of the proteins these genes express, so potentially some drugs out there [could be used in IVF treatment.]"
Perry suggested inhibition of Chek2 during hormone therapy to stimulate maturation of oocytes might increase the number of eggs that develop and can be harvested for IVF. "There are women with natural loss of function in Chek2, so it can be tolerated. There is an increased risk of breast cancer, but that is across life; for IVF we are talking [days]," Perry said.
The researchers also used public databases to examine the health impacts of variation in the 290 menopause-related genetic variants they identified. They found that each year of genetically delayed menopause increases the risk of hormone-dependent cancers, as previously observed in epidemiological studies.
Genetic variants that delayed menopause increased bone density. There was no effect on the risk of cardiovascular disease, lipid levels or body mass, but there was a reduced risk of type 2 diabetes when age at menopause was delayed.
Perry told BioWorld Science that is the first time this link has been made. "It's a new association that's not been on the radar before ... We're not sure what the mechanism is, but it's something we are going to be very motivated to understand." Perry said.
Last month, Perry published data on other novel genetic variants he has identified that increase the risk of developing typing 2 diabetes, including one variant that leads to loss of function of Chek2 on chromosome Y in men.
There is some overlap between the genes identified in the reproductive aging study and those previously pinpointed as having links to type 2 diabetes, said Perry. "That intersection is where we will be looking to take forward our experimental work," he said.