Study finds genetic signals that could be used to predict early menopause

TO big new to study scanned the genes of hundreds of thousands of women close to menopausal age and showed hundreds of genetic signals that researchers say could help predict and prevent early menopause, as well as treat infertility and improve reproductive health in women. women in the future.

The study, published in Nature, identified 290 genetic variants, many of them part of a DNA repair pathway associated with the age at which women enter menopause. The 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, might influence the reproductive lives of women.

The average age at which women begin menopause is approximately 51 years, and it is caused by a decrease in ovarian reserve, the ability to produce healthy eggs. But there is a significant variation in the age of onset of menopause, determined by genetic and environmental factors. Although environmental factors that influence menopause, such as smoking and chemotherapy, are well studied, genetic factors remain a black box.

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Studying the underlying biology and genetics of menopause has proven difficult because a woman’s egg supply is formed primarily 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 UK and author of the new study. “No one is going to biopsy a woman’s ovaries, it is very valuable tissue.”

To get around these difficulties, the researchers looked for genetic studies called genome-wide association studies, or GWAS. Two such previous studies had identified around 60 genetic regions associated with the time of menopause.

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Now, the multi-agency team has examined the genes of a much larger group of women, some 200,000, between 40 and 60 years old, and found almost 300 genetic signals associated with the time of menopause. 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 cell health or induce cell death if necessary. Still, the researchers were surprised by the prevalence of this pathway in their findings. “I don’t know if other traits have found this level of enrichment for a particular process,” Murray said.

Using the identified variants, the authors produced a risk score to see if they could predict which individuals were likely to have premature ovarian failure, which occurs when women reach menopause before age 40. Although it was a weak predictor, the risk score identified women who began menopause in their 40s better than the state of smoking.

Two DNA repair genes, Chek1 and Chek2, stood out for their strong association with the time of menopause. Women who lacked a functional Chek2 protein went through menopause three and a half years later than those with normal Chek2, and females raised without the Chek2 gene had more eggs than normal mice when they were older, effectively extending their reproductive lives.

On the other hand, the introduction of a copy of the Chek1 gene in the mice also extended their reproductive life, but by allowing the 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, a cell biologist at Johns Hopkins University and a professor at the National University of Singapore who studies cellular processes of development.

In the future, the researchers hope that these findings may lead to therapies to extend fertility in women, although it may not be a straightforward process, Murray said. While early menopause was associated with an increased risk of type 2 diabetes and poorer bone health, it was also associated with a lower risk of breast and ovarian cancer. To avoid the detrimental effects of delaying menopause, the researchers suggest that therapies could be used in the short term, such as 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] they’re a little scary to manipulate because [by inhibiting them] I could have cancer, ”said Li, who was not involved in the study but has collaborated with Perry. “Other avenues could be better and safer targets for intervention.”

More simply, the findings could also be used to give women more information about the approximate age at which they would go through menopause. Predictions about the age of menopause could inform women about their risk of developing conditions such as breast cancer and help them make decisions about when to have children, which could help them avoid unnecessary procedures, such as infertility treatments.

But because most of the study was conducted in women of European descent, 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 looked at women of East Asian descent, it found that many of the genetic cues remained, but the effect size of these genetic regions at menopause was different from that of women of European descent.

Murray hopes that future studies can improve the prediction of the age of menopause by also including non-genetic factors known to influence ovarian reserve, such as smoking. Researchers are hopeful that women’s reproductive health will finally receive the attention it deserves, which could open the door to more studies and ultimately better health outcomes.

“I think with studies like this, we are making a lot of progress,” Welt said. “Let’s look at all female reproductive problems with genetics, because, unfortunately, it has been a neglected aspect of medicine.”

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