A large new study scanned the genes of hundreds of thousands of women near the age of menopause and turned up hundreds of genetic signals that the researchers said might help predict and prevent early menopause, as well as treat infertility and improve women’s reproductive health in the future.
The study, published in Nature, identified 290 genetic variants, many of them part of a pathway that repairs DNA, associated with the age at which women enter menopause. Researchers also found that changing the levels of two of these DNA repair genes delayed menopause in mice. The study broadens the understanding of how genes, specifically those in the DNA-damage response pathway, could influence the reproductive life span in women.
The average age at which women start menopause is about 51 years, and is brought on by a decrease of ovarian reserve, the capacity to produce healthy eggs. But there is significant variation in the age of menopause onset, determined by genetics and environmental factors. Although the environmental factors that influence menopause, like smoking and chemotherapy, are well-studied, the genetic factors had remained a black box.
Studying the underlying biology and genetics of menopause has proven difficult because a woman’s supply of eggs are mostly formed before birth and studying it in adult humans often means taking a sample of ovarian tissue. “If you were studying muscle or skin, you can take a biopsy of those tissues,” said Anna Murray, a geneticist at the University of Exeter in the U.K. and author of the new study. “Nobody’s going to biopsy a woman’s ovaries — it’s very precious tissue.”
To get around these difficulties, researchers looked to genetic studies called genome-wide association studies, or GWAS. Two such previous studies had identified around 60 genetic regions associated with the timing of menopause.
Now the multi-institutional team looked at the genes of a much larger group of women, about 200,000, between 40 and 60 years old, and found nearly 300 genetic signals associated with menopause timing. Similar to the results of their previous studies, many of the genetic regions they identified are involved in processes that respond to DNA damage to maintain cells’ health or induce cell death if necessary. Still, the researchers were surprised by how prevalent this pathway was in their findings. “I don’t know if other traits have found this level of enrichment for one particular process,” said Murray.
Using the identified variants, the authors produced a risk score to see if they could predict which individuals were likely to have premature ovarian insufficiency, which occurs when women reach menopause before the age of 40. Although it was a weak predictor, the risk score identified women who started menopause by 40 better than smoking status.
Two DNA-repair genes, Chek1 and Chek2, stood out for their strong association with menopause timing. Women who lacked a working Chek2 protein had menopause three and a half years later than those who had normal Chek2, and female mice bred without the Chek2 gene had more eggs than normal mice when they were older, effectively extending their reproductive life span.
On the other hand, introducing a copy of the Chek1 gene into the mice also extended their reproductive life span, but by enabling production of more eggs after birth, which took longer to deplete. These different mechanisms “really highlight the complexity in the processes that go into the ovarian reserve,” said Rong Li, cell biologist at Johns Hopkins University and professor of the National University of Singapore who studies cellular processes of development.
In the future, researchers hope these findings could lead to therapeutics to extend fertility in women, though it may not be a straightforward process, Murray said. While early menopause was associated with increased risk of type 2 diabetes and worse bone health, it was also associated with decreased risk of breast and ovarian cancer. To avoid detrimental effects of delaying menopause, researchers suggest that therapeutics could be used in the short-term like targeting certain genes to enhance egg production during IVF cycles, for example.
Targeting DNA-repair genes with treatments could also have unintended consequences. Li suggests that other genes may be better targets. “[DNA-damage response genes] are a bit scary to manipulate because [by inhibiting them] you could get cancer,” said Li, who was not involved with the study but has collaborated with Perry. “Other pathways might be better and safer targets for intervention.”
More simply, the findings could also be used to provide women with more information about the approximate age when they would get menopause. Predictions about menopause age could inform women of their risk of developing conditions like breast cancer and help their decisions about when to have children, which could help them avoid unnecessary procedures, like infertility treatments.
But because most of the study was done on women of European ancestry, the findings need to be replicated in different populations, said Corrine Welt, an endocrinologist at the University of Utah who studies the genetics of early menopause and who was not involved in the study. When the study did look at women from East Asian ancestry, it found that many of the genetic signals held up but the size of the effect of these genetic regions on menopause timing was different than those in women with European ancestry.
Murray hopes future studies could improve menopause age prediction by also including non-genetic factors that are known to influence ovarian reserve like smoking. Researchers are hopeful that women’s reproductive health is finally getting the attention it deserves, which could open the door for more studies and ultimately better health outcomes.
“I think with studies like this, we are making a lot of headway,” said Welt. “Let’s study all the female reproductive problems with genetics, because, unfortunately, it’s been an underserved aspect of medicine.”
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