Genetic variation associated with early or late menopause

Disease and treatment 24. sep 2021 3 min Professor in Molecular Genetics, NNF Young Investigator Eva Ran Hoffmann Written by Kristian Sjøgren

Researchers in Denmark have identified 290 genetic variants that contribute to determining whether women can remain fertile until they are 35 or 55 years old or somewhere in between. The discovery may also help to identify women who could freeze their eggs for use later in life.

Women go through natural menopause at different ages. Women’s reproductive longevity averages 51 years, but some women are no longer fertile in their thirties or remain fertile as late as their sixties.

A hereditary component governs menopause. If a woman’s mother has late menopause, her daughters follow the same pattern.

New research in Denmark now shows which genetic variants are associated with the hereditary component.

One gene plays a major role, and this might be used to help women who are otherwise struggling to conceive.

“Reproductive longevity depends on several factors, including environmental factors. For example, smoking, chemotherapy and immune disorders contribute to earlier menopause. However, menopause also has a clear genetic component, and this study identified 290 genetic variants that account for about 30% of the overall heritability in reproductive longevity,” explains a researcher behind the study, Eva Hoffmann, Professor at the Department of Cellular and Molecular Medicine, University of Copenhagen.

The research done by researchers in Denmark together with collaborator in the UK and Spain has been published in Nature.

Mapped DNA of 550,000 women to identify genes influencing the timing of menopause

Eva Hoffmann and colleagues examined the DNA of 550,000 women using data from the UK Biobank and 23andMe in the United States. In both databases, the women had had their genome sequenced and had completed questionnaires that included questions on the timing of menopause.

The women in the study were 40–70 years old, and the researchers compared the genomic information with the questionnaire responses to detect all the genetic variants associated with either early or late menopause.

Genetic variants are small differences in genes that makes them behave a little differently. The variants can strongly influence the biology in the body, such as the risk of developing various diseases, becoming tall or short, being more prone to becoming overweight or, as in the new study, adjusting the timing of menopause.

“There is naturally great interest in identifying the factors that affect the reproductive longevity of half the global population. Various rare genetic variants trigger very early menopause, but we wanted to identify the genetic variants that are completely normal and yet influence the timing of menopause,” says Eva Hoffmann.

Genetic variant delays menopause by up to 4 years

The study shows that 290 genetic variants influence the timing of menopause.

Most are not important, but a few are very important, especially CHEK1 and CHEK2.

A woman with CHEK2 will on average go through menopause 3.5–4 years later than a woman without it – although fewer than 1% of the women in the study carried the CHEK2 variant.

“It is fantastic that we can now study the individual genes and determine what they actually do in the body. We can thus also learn more about the biological mechanisms in the body that determine a woman’s reproductive longevity,” explains Eva Hoffmann.

Genetic variants also linked with DNA repair

Eva Hoffmann says that some genes have a role in integrating and determining repair and cellular response mechanisms.

“In particular, the mechanisms behind DNA repair seem to strongly affect the timing of menopause – and this also applies to various signalling networks. We found that 58 of the identified genetic variants influence cellular signalling and signals that trigger cell death,” says Eva Hoffmann, adding that, in relation to fertility treatment, this provides researchers with additional knowledge on how problems might arise that prevent women from conceiving.

“We can examine when these networks function and when they do not and how this affects the chances of getting pregnant,” she explains.

Gene may potentially be used in fertility treatment

In addition, the researchers investigated how inserting an extra copy of CHEK1 into mice’s DNA affected the mice.

If the mice had an extra CHEK1 gene, the mouse pups were born with more eggs in their ovaries, which extended their reproductive longevity. CHEK1 is involved in repairing DNA damage. By contrast, CHEK2 eliminates eggs that appear to contain DNA damage.

Among mice without the CHEK2 genetic variant, fewer eggs are eliminated, thereby enabling greater reproductive longevity. The same probably applies to women.

“This also means that inhibiting CHEK2 among women undergoing fertility treatment may enable us to remove more eggs from these women for in vitro fertilisation,” says Eva Hoffmann.

Identifying early menopause and freezing eggs

Eva Hoffmann says that, in addition to understanding and having better insight into the biological mechanisms governing menopause, the results can also be used to develop analytic tools to estimate a woman’s reproductive longevity.

For a woman whose mother went through early menopause, examining the various genetic determinants of menopause may be relevant to assess whether she risks undergoing menopause as early as her mid-thirties.

“Identifying women at high risk of early menopause will enable them to make choices, such as starting a family early, or if available, freeze eggs or ovarian tissue to enable them to have children later in life if they wish,” concludes Eva Hoffmann.

Genetic insights into biological mechanisms governing human ovarian ageing” has been published in Nature. In 2015, the Novo Nordisk Foundation awarded a grant to Eva Hoffmann for the project Mapping the Genomic Landscape in the Human Germline. Eva Hoffmann was elected as a member of the European Molecular Biology Organization, a lifetime honour in recognition of her extraordinary results within the biological sciences.

Chromosomes are rearranged and organized into new sets to create diversity as they are passed from parent to offspring through the germline. The genet...

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