The research team began by analyzing genetic data from 106,973 post-menopausal women participating in the UK Biobank study. Their focus was on rare genetic mutations that lead to a loss of protein and how these mutations affect when menopause occurs. Although these genetic mutations are uncommon in the population, they have a significantly greater impact on menopause timing—five times more than any commonly recognized genetic variant.
Recent studies have identified four genes that have the most substantial known effects on the timing of menopause, shedding light on the relationship between menopause timing and cancer risk.
Genes exist in pairs, and women with only one functional copy of the four newly identified genes (ETAA1, ZNF518A, PNPLA8, PALB2) experience menopause 2 to 5.5 years earlier than the average.
This significant research, published in Nature, received funding from the Medical Research Council and Wellcome. Initially, the team examined variations in the genetic data from the UK Biobank’s large group of post-menopausal females. They concentrated on rare genetic alterations that lead to protein loss and their effects on menopause timing.
Though these genetic alterations are rare, their effects on menopause timing are far more pronounced compared to any previously known common genetic variants. The most significant impact was observed with genetic variants in ZNF518A, found in roughly one in every 4,000 women, which significantly shortened reproductive lifespan more than other recognized genes.
Understanding the influence of these genes helps scientists gain insights into the biological processes associated with menopause and their implications for other diseases.
Professor Anna Murray, co-lead of the study from the University of Exeter Medical School, remarked, “For many years, menopause research has been limited, but this area is rapidly advancing. The timing of menopause greatly impacts women as they navigate their careers and personal lives, and understanding these genetic factors may lead to future treatments that could extend reproductive lifespan.”
When DNA damage is not repaired in egg cells, it can lead to their death. The rate of egg loss is a determining factor in when menopause occurs. Previous research from the team indicated that many genes influencing menopause timing likely do so by affecting the genetic stability of eggs. Similar factors influence other cell types as well. In this new study, they found that numerous genes associated with menopause timing are also linked to cancer risk. Changes in the BRCA1 and BRCA2 genes were noted to result in earlier menopause alongside a heightened cancer risk.
The mechanism proposed also applies to a fifth gene associated with menopause timing, SAMHD1. The researchers discovered that variations in this gene can lead women to experience menopause more than a year later than typical. Additionally, they identified that variations in this gene predispose both men and women to various cancers for the first time.
Professor John Perry, co-lead from the MRC Epidemiology Unit at the University of Cambridge, added, “Previous studies suggest that the female ovary ages faster than any other organ, providing a model to study the biology of aging as a whole. Our recent findings support this notion, illustrating that exploring ovarian aging can improve our understanding of infertility, reproductive disorders, and the fundamental processes influencing DNA damage and cancer risks in the general population.”
Using data from the 100,000 Genomes Project, led by Genomics England and NHS England, the researchers also found that mothers with a high number of genetic variants linked to earlier menopause tended to pass on more new DNA changes to their children. The authors believe this occurs because the relevant genes help in DNA repair, suggesting that their functionality may be impaired in the ovaries, allowing for new genetic changes to happen in egg cells.
Dr. Hilary Martin, a co-lead from the Wellcome Sanger Institute, pointed out, “New genetic changes in egg or sperm cells account for all the genetic variation in humans, leading to differences among individuals in traits, behavior, and disease susceptibility. Previously, we lacked knowledge about what influences these new DNA alterations, aside from parental aging. This study marks the first instance where existing common DNA variations have been linked to the frequency of these changes.”
