Connection of genes to premature menopause more complex than thought

Genetic variants previously thought to cause premature menopause are unlikely to be solely responsible for the condition, researchers have revealed.

Premature menopause, or premature ovarian insufficiency (POI), which occurs under the age of 40 affects roughly one percent of women and is a frequent cause of female infertility. A research team has demonstrated that genetic variants previously reported to be a monogenic cause of the condition may not be sufficient for clinicians to make a genetic diagnosis of POI.

'The presence of specific genetic variants in multiple women who experience premature menopause has led to the assumption that they are causing the condition,' said senior author on the study, Professor Anna Murray, from the University of Exeter Medical School. 'But we have shown that these gene variations are also found in women with a normal age of menopause.'

Researchers from the University of Exeter and the University of Cambridge published their findings in Nature Medicine where they assessed one of the largest samples of women with premature menopause to date. The team analysed exome sequencing data from 104,733 post-menopausal women in the UK Biobank, 2231 of whom reported experiencing natural menopause before the age of 40.

By assessing genetic variation in 105 proposed POI genes, 40 of which are reported to have an autosomal dominant pattern of inheritance, researchers revealed that nearly all women (98 percent) who carried at least one of these 40 gene variants had the menopause over the age of 40. Thus, the researchers suggest that the variants in the proposed POI genes are unlikely to be the cause of premature menopause.

Professor Murray also revealed that much of the information researchers have on the genes and genetic variants currently implicated in POI came from studies in animal models or small human cohorts. 'No one had looked at how these variants caused the disease in a large human population,' she told GenomeWeb.

Findings from this study now suggest that POI cases are less likely to be monogenic and more likely to be the result of genetic variation in multiple genes, as well as various non-genetic risk factors.

'Although genetic variation in the studied genes were not sufficient to cause very early menopause, we did identify genetic drivers that had a much more subtle impact on reproductive longevity,' noted co-lead researcher Stasa Stankovic, PhD candidate from the University of Cambridge. 'For example, women carrying genetic variation in TWNK and SOHLH2 genes experienced menopause up to three years earlier than the general population.'

A more complete understanding of the genetic complexity of POI is critical for developing new diagnostic approaches for the condition. Future efforts aim to ensure women receive appropriate treatment and guidance for POI, minimising 'potential misdiagnoses and inappropriate genetic counselling'.