Using data from the UK Biobank the researchers analyzed the rare variants in the protein coding region in the genomes of 106,973 women. They identified rare variants that disrupt the function of nine genes that are associated with ANM. Four of these were already known while five were linked to ANM for the first time. Three of the five new genes (PALB2, ETAA1 and HROB) are involved in the DNA damage response (DDR) while two (PALB2 and ZNF518A) are not, suggesting new pathways for ovarian aging. Previous studies have identified common genetic variants that are associated with ANM and also regulate the DDR, where minimal damage to the genome of an egg leads to repair and irreparable damage leads to its destruction. The findings provide confirmation that the DDR influences ANM by either maintaining or depleting the egg reserve. The effect of the rare variants was up to five times larger than that previously found for common variants in five of the genes (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). Individuals carrying a rare mutation in ZNF518A experienced ANM about 5.6 years earlier and had later onset of menstruation by 0.56 years, whereas those with damaging alleles in SAMHD1 had menopause 1.35 years later.

Because previous work shows that ovarian aging is linked to cancer susceptibility and, notably, SAMHD1 is disrupted in many cancers, the authors next analyzed both men and women for the effect of ANM-associated genes on cancer outcomes. They showed that the damaging variants in SAMHD1 were associated with an increased risk of developing any kind of cancer in both groups, as well as sex-specific cancers such as prostate cancer in men and hormone-sensitive cancers in women.