The genetics of menopause

While the median age of menopause is 51 years, primary ovarian insufficiency (POI) premature menopause can occur at 40 years or younger and late menopause can occur as late as 62 years. We know that POI is related to adverse health conditions including increased risk of CHD, osteoporosis, cognitive decline and mortality.[1] But why does premature menopause occur? Nutritional status is not considered to affect age of menopause. Similarly, menopause shows no decennial or centennial trends. So, what is causing this variation?

 

The genetic impact

Presenting at COGI 2018, Prof. Joop Laven explained that over 50% of the variation in age of menopause is caused by genetic variance.

However, pinpointing the specific genetic variants associated with menopause is complex. Results from genetic studies are often underpowered with inconsistent results. One genome-wide linkage study identified only one variant approaching genome-wide significance (rs6543833)[2], while another study concluded that the genetic architecture related to age of menopause involves a large number of rare, low frequency and common variants.[3]

However, with the advances in next generation sequencing (NGS) there is hope. Prof. Laven shared data from two recent genome-wide association studies (GWAS), which suggest that genes affecting ovarian function seem to play a role in DNA maintenance and DNA repair, particularly in repairing double strand breaks (DSB).[4],[5] Somatic cell ageing is associated with decreased effectiveness of DNA repair and Prof. Laven explained that it is key to understand that these genes therefore affect both somatic cell ageing and germ line ageing.

He suggested the following paradigm: The ageing of the soma as a result of inefficient DNA repair may be responsible for loss of ovarian function. This means that somatic ageing could be seen as a primary driver of POI.

 

Reproductive success, menopause and longevity

Interestingly, Prof. Laven also explained that genetic factors involved in DNA repair and maintenance are also common between reproductive performance, age of menopause as well as longevity.[5] He discussed that good reproductive health seems to be linked to good physical condition of the soma. As such, decreased fertility appears to be strongly associated with reduced health status.

So, what does this mean? Well, perhaps decreased fertility may be able to be used as a predictor of general health in later life to further support the future of individualised, precision medicine.  


Sources:

[1] The timing of the age at which natural menopause occurs. Obstet Gynecol Clin North Am. 2011;38(3):425-40.

[2] Sonya M. Schuh-Huerta, Nicholas A. Johnson, Mitchell P. Rosen, et al; Genetic variants and environmental factors associated with hormonal markers of ovarian reserve in Caucasian and African American women, Human Reproduction, Volume 27, Issue 2, 1 February 2012, Pages 594–608, https://doi.org/10.1093/humrep/der391

[3] Perry JRB, Murray A, Day FR, Ong KK. Molecular insights into the aetiology of female reproductive ageing. Nat. Rev. Endocrinol. 2015;11:725–734. doi: 10.1038/nrendo.2015.167.

[4] Jiao, X., et al. (2018). "Molecular Genetics of Premature Ovarian Insufficiency." Trends Endocrinol Metab 29(11): 795-807.

[5] Laven, J. S. E., et al. (2016). "Menopause: Genome stability as new paradigm." Maturitas 92: 15-23.