Genes With a Strong Influence on the Age of Menopause Onset Are Also Associated With Cancer Risk

New research has discovered four genes with some of the largest effects on the timing of menopause known to date, and provided new insights into the links between the timing of menopause and cancer risk. The large-scale analysis was funded by the Medical Research Council and Wellcome and published in Nature.

Better Understanding of Biological Mechanisms Underlying Menopause and Links to Other Diseases

Genes come in pairs, and if women have only one functional copy of the four newly identified genes (ETAA1, ZNF518A, PNPLA8, PALB2), they will experience menopause between two and five and a half years earlier than average. The team first examined variations in the data in the genetic sequencing of 106,973 postmenopausal female participants in the UK Biobank study. The researchers focused on rare types of genetic changes that result in the loss of the protein and examined their effects on the onset of menopause.

The genetic changes studied are rare in the population, but their influence on menopause is five times greater than the influence of all previously identified common genetic variants. The strongest effect was found in gene variants in ZNF518A, which occurred in only one in 4,000 women. These variants shortened reproductive lifespan more than most previously identified genes. The discovery of the effects of genes allows scientists to better understand the biological mechanisms underlying menopause and to establish links with other diseases.

For decades, menopause was poorly understood, but now it is a rapidly developing field of science. According to the researchers, the timing of menopause has a huge impact on women as they plan their careers and lives, and understanding the genetic changes is of particular interest in terms of potential treatments that could extend reproductive life in the future.

If unrepaired DNA damage occurs in eggs, they can die. The rate at which egg cells are lost determines when women will experience menopause. The team’s previous work has shown that many genes that influence the timing of menopause likely do so by affecting the genetic integrity of egg cells. The same factors affect other cells and tissue types in parallel, and in this new study, the team found that many of the genes associated with the timing of menopause are also risk factors for cancer. These include changes in the genes BRCA1 and BRCA2, which lead to an earlier menopause and also to an increased risk of cancer.

Changes in a Particular Gene Increase the Risk of Cancer in Menopause

This is thought to be the process at work in a fifth new gene linked to the timing of menopause (SAMHD1). The team discovered that changes in this gene can cause women to go through menopause over a year later than average. The researchers also found for the first time that changes in this gene cause a predisposition to various cancers in both men and women. Previous research suggests that women’s ovaries age faster than other organs in the body, and this is a model system for understanding the biology of aging in general. The latest research builds on this concept, demonstrating that studying ovarian aging will not only lead to a better understanding of the biology behind infertility and other reproductive disorders, but will also improve our understanding of fundamental processes that regulate DNA damage and cancer risk in the general population.

Next, using data from the 100,000 Genomes Project, led by Genomics England and NHS England, the team found that mothers with high numbers of genetic variants that lead to an earlier menopause tended to have more new changes in the DNA they pass on to their children. The study authors believe that this is because the relevant genes are involved in repairing DNA damage, so this function in the ovaries could be impaired, allowing new genetic changes to occur in the eggs.

According to Dr. Hilary Martin, one of the study leaders from the Wellcome Sanger Institute, new DNA changes in the egg or sperm are the cause of all genetic variations in humans and contribute to differences between individuals in their appearance, behavior and risk of disease. Until now, very little was known about what influences these new DNA changes, apart from the age of the parents. This is the first time that existing overall DNA variation has been shown to influence the rate of these changes.