Genomic analysis

Topic: Genomic analysis identifies variants that can predict the timing of menopause

A broad analysis has identified genetic variants that influence age at natural menopause. The results implicate mechanisms such as DNA-damage repair and give insights into the potential for predicting and treating early menopause.

Menopause is the permanent cessation of menstrual cycles in women following the loss of ovarian function. It occurs, on average, between 47 and 52 years of age globally, but around 4% of women undergo it before the age of 45 (early menopause) or even 40 (primary ovarian insufficiency; POI). Being able to predict when menopause will occur would give women and their partners greater flexibility in choosing when to have a child. This knowledge, and treatments to delay menopause, might be particularly welcomed by women at high risk of early menopause or POI. Ruth et al. now report genetic findings that could bring us a step closer to predicting and treating early menopause.

Age at natural menopause (ANM) is determined by the complex interaction of both non-genetic and genetic factors. Non-genetic factors associated with earlier ANM include poor childhood nutrition and smoking, whereas being overweight is associated with later ANM1,2. Genetic factors are thought to account for about 50% of the variation in menopausal timing. Previous genetic studies have implicated a role for DNA-damage-response (DDR) mechanisms in the timing of menopause. DDR is a molecular process that is crucial for the error-free replication of cells, including the generation of egg cells in the ovary, and for the repair of DNA damage caused by environmental factors such as cigarette smoke.

Ruth et al. conducted the largest genetic analysis so far in women whose ANM occurred between the ages of 40 and 60 years, testing millions of common genetic variants from across the genome for an association with ANM. Differences in genetic ancestry could distort results, and the analyses were therefore initially restricted to 200,000 women of European ancestry. Approximately half of this sample was derived from the UK Biobank, a large, population-based study containing extensive clinical, biological and genomic data. Ruth et al. found 290 independent areas of the genome that contained common genetic variants associated with ANM, a fivefold increase from previous results10. The impact of each variant on ANM varied from very small (3.5 weeks) to considerable (1.5 years).

Topic Discussed: Genomic analysis identifies variants that can predict the timing of menopause

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