NEW YORK – A team from the University of Exeter and other centers in the UK, Iceland, Australia, and Denmark has tracked down rare protein-coding variants associated with age at natural menopause (ANM), including genes with ties to reproductive lifespan, DNA damage repair, and cancer risk.
"This study provides evidence of genetic links between age of menopause and cancer risk," co-senior and co-corresponding author Anna Murray, a researcher affiliated with the University of Exeter Medical School, and her colleagues wrote in Nature on Wednesday, noting that common variants unearthed in past studies account for roughly one-third of ANM heritability and an estimated 10 percent to 12 percent of ANM variation.
The new work focused on rare variation in an unselected population enrolled through the UK Biobank project, building on common variant findings that Murray and her colleagues reported in a paper in Nature in 2021.
Using exome sequence data for 106,973 postmenopausal European ancestry women from the UK Biobank project, the researchers searched for rare protein-coding variants linked to ovarian aging, identifying ANM-associated rare protein-truncating, missense, or damaging variants affecting some of the same genes affected by the 290 common variants linked to ovarian aging by GWAS.
In particular, the team saw an overrepresentation of rare, ANM-associated coding variants in nine genes, including five genes containing variants with effect sizes that surpassed those of common variants by around fivefold: PALB2, SAMHD1, ZNF518A, PNPLA8, and ETAA1.
"What we find in this latest study is that many of the same loci are coming up with exome associations, but the effect sizes are much larger," Murray said in an email. She further noted that the new exome-centered results complement prior common variant analyses by offering additional support for candidate genes involved in ANM and related processes.
For example, the investigators' analysis highlighted a role for genes involved in cancer and/or DNA damage repair, including SAMHD1, CHEK2, and the BRCA2 localization and stability-related gene PALB2, which has been implicated in Fanconi anemia and cancer risk. More broadly, such findings pointed to a relationship between DNA damage, declining ovarian reserve, and ovarian aging.
Such results were backed up by the team's subsequent analysis on sequenced parent-child trios from the 100,000 Genomes Project, which found an uptick in de novo mutations in children born to mothers carrying common variants implicated in earlier-than-usual ANM, though the same early ANM-related variant-de novo mutation pattern did not turn up in an analysis of published Decode Genetics data.
"The study confirms the importance of DNA damage response in determining ovarian aging, but also reveals some fascinating new genes where we aren't sure yet what the mechanism might be," Murray said.
For example, she noted that 28 study participants who carried loss-of-function alterations in a gene called ZNF518A tended to go through menopause more than five years earlier, on average, than noncarriers. The loss-of-function ZNF518A changes also coincided with a slightly later start to puberty, the researchers reported, with average age of menarche occurring more than half a year after that found in noncarriers.
"ZNF518A is a transcription factor that binds to multiple sites in the genome and when we looked closer at the sites it binds to, we saw enrichment for regions we had identified in GWAS for menopause and menarche in our previous studies," Murray said. "So, this may be gene that regulates ovarian development and oocyte depletion by regulating multiple genes in the genome."
On the other hand, the investigators identified rare variants in a handful of genes — CHEK2, HELB, and SAMHD1 — that coincided with delayed ovarian aging and later ANM, suggesting it may be possible to find clues for not only understanding the ovarian aging process but also for developing related treatment strategies.
"What we see is that some genes decrease menopause age while others delay it, and we think these differences relate to different the effects on either DNA damage repair or apoptosis checkpoints in oocytes," Murray explained. "The genes that delay menopause could be good targets for fertility preservation."