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Menopause Timing Influenced by Hundreds of Genetic Loci, New GWAS Finds

NEW YORK – Researchers have uncovered hundreds of genetic loci that influence when a woman undergoes menopause. The findings could eventually be used to guide fertility decisions and, possibly, treatments.

The timing of menopause, which generally occurs between 47 and 52 years of age, is influenced by both environmental factors as well as genetics. Women with premutations in FMR1, for instance, are at increased risk of primary ovarian insufficiency, or menopause before the age of 40.

In a new genome-wide association study, published in Nature on Wednesday, an international team of researchers uncovered nearly 300 genetic loci linked to age at natural menopause that could broadly predict early menopause. These loci further implicated DNA damage response mechanisms in ovarian aging, and targeting certain DNA damage response genes in mice could extend their fertility.

"The principle aim of our study was to improve our understanding of the biological processes involved in female reproductive aging," co-senior author Anna Murray from the University of Exeter said during a press briefing. "This has traditionally been a difficult area of study."

Using genome-wide array data from 201,323 women of European ancestry, the researchers identified 290 loci associated with age at natural menopause and found that their effect size ranged from a few weeks to more than three years. They estimated that these loci together account for about a third of the genetic variation in age at menopause, and for about 12.5 percent of the overall variation.

The researchers further replicated these signals in an independent sample of 294,828 women of European ancestry, and in a cohort of 78,317 women of East Asian ancestry, though they noted differences in effect sizes and allele frequencies within the Asian cohort.

Based on these loci, the researchers developed a polygenic risk score to identify women at risk of early menopause. "The reason we'd like to be able to identify women who might have earlier menopause would be to help them plan their lives and to help them make informed choices," co-first author Katherine Ruth, also from Exeter, said during the briefing, adding that this "might help women to avoid infertility treatments in the future, which are often expensive and fairly unpleasant."

She added that the score was not able to identify all women who experienced early menopause but did "a fairly reasonable job" in identifying some women at increased risk of the condition. She and her colleagues are working to improve the predictive ability of the score, she said.

Many of these 290 loci are in, or influence, genes with roles in DNA damage response, including loss-of-function variants in DNA damage response-associated genes.

The researchers found that manipulating DNA damage response pathways could extend reproductive lifespan in mice. An extra copy of CHEK1, for instance, led to female pups with a higher number of oocytes, possibly due to enhanced DNA repair. Meanwhile, female mice lacking CHEK2 had a slower decline in oocytes during their lives, which the researchers attributed to the inhibition of cell death.

These findings suggest possible approaches for treating infertility. "What our study shows is that it's possible that targeted, short-term inhibition of these pathways during IVF treatment could help some women respond better," co-senior author Eva Hoffmann from the University of Copenhagen said during the briefing, noting there are scientific and safety concerns to be addressed before trying such an approach in people.

The researchers additionally examined the health effects of early menopause. Through a Mendelian randomization analysis, they found earlier menopause was linked to an increased risk of fractures and type 2 diabetes, but also to a lower risk of hormone-dependent cancers, likely due to a shorter lifetime exposure to sex hormones.

In an accompanying commentary in Nature, the University of Oxford's Krina Zondervan wrote that although the effects of many factors affecting reproductive age span remain opaque, this study provides "a considerable advance in our understanding of the genetic and molecular mechanisms" affecting age at menopause.

In addition to refining their polygenic risk score, the researchers are beginning to put together a larger and more diverse cohort of women to ensure the findings are reproducible across ancestry groups.