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Exome Sequencing Study Suggests Early Menopause May Not Be Monogenic

NEW YORK — Researchers have found that gene variants that were thought to cause premature ovarian insufficiency may not be fully responsible for the condition.

Primary ovarian insufficiency (POI) occurs when the ovaries stop functioning normally before age 40 and often leads to infertility. Up until now, variants in one of more than 100 genes associated with the condition were thought to be monogenic causes of POI, and clinicians would consider the presence of one of these gene variants a genetic diagnosis of POI.

However, in a study published in Nature Medicine on Thursday, researchers from Exeter University and elsewhere examined the penetrance of these variants to find that nearly all women who carried variations in these genes in fact went through menopause after the age of 40.

"The presence of specific genetic variants in multiple women who experience premature menopause has led to the assumption that they are causing the condition — but we have shown that these gene variations are also found in women with a normal age of menopause and therefore in many cases the link could just be coincidence," co-corresponding author Anna Murray, professor of human genetics at the University of Exeter's medical school, said in a statement.

Murray noted that a lot of the information about the 100 genes implicated in POI came from mouse studies or small human cohorts. "No one had looked at how these variants caused the disease in a large human population," she told GenomeWeb.

For this study, Murray and colleagues analyzed exome sequencing data from more than 104,733 women in UK Biobank, of whom 2,231 reported experiencing menopause before the age of 40.

They found that nearly all heterozygous copies of previously reported POI gene variants could be found in reproductively healthy women.

Further, while previous work from their laboratory had shown that heterozygous loss-of-function (LOF) of ZNF518A had a large effect on menopause timing, this study did not substantiate those findings. This study showed that ZNF518A LOF carriers reported menopause only six years earlier than noncarriers and only 12 percent experienced POI. "Taken together, our observations suggest that fully, or even largely, penetrant [autosomal dominant] inheritance effects are likely to cause very few cases of POI," the authors wrote.

These findings suggest that current ways of genetically diagnosing POI could be misinterpreted and may erroneously suggest that relatives may also be at risk, according to Murray. "It now seems likely that premature menopause is caused by a combination of variants in many genes, as well as non-genetic factors," she said.  

Murray said the next step would be to conduct a similar study in other cohorts of women from different ethnicities.

Meanwhile, future studies should take into consideration the genetic complexity of POI in the development of new diagnostics to minimize potential misdiagnoses and inappropriate genetic counseling, the authors wrote.