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.

研究人员使用来自英国生物样本库的数据分析了 106,973 名女性基因组中蛋白质编码区的罕见变异。他们发现了破坏与 ANM 相关的 9 个基因功能的罕见变异。其中 4 例是已知的，而 5 例是首次与 ANM 有关。五个新基因中的三个 （PALB2、ETAA1 和 HROB） 参与 DNA 损伤反应 （DDR），而两个 （PALB2 和 ZNF518A） 则不参与，这表明卵巢衰老的新途径。以前的研究已经确定了与 ANM 相关并调节 DDR 的常见遗传变异，其中对卵子基因组的最小损伤会导致修复，而无法修复的损伤会导致其破坏。研究结果证实，DDR 通过维持或消耗卵子储备来影响 ANN。罕见变异的影响比以前发现的五个基因 （ETAA1、ZNF518A、PNPLA8、PALB2 和 SAMHD1）的常见变异的影响大五倍。携带罕见突变的个体ZNF518A大约提前 5.6 年经历 ANM，月经开始晚 0.56 年，而那些在 SAMHD1 中具有破坏性等位基因的个体在 1.35 年后更年期。

因为以前的工作表明卵巢衰老与癌症易感性有关，而且值得注意的是，SAMHD1 在许多癌症中被破坏，所以作者接下来分析了男性和女性 ANM 相关基因对癌症结果的影响。他们表明，SAMHD1 中的破坏性变异与两组患任何类型癌症的风险增加有关，性别特异性癌症（如男性前列腺癌和女性激素敏感性癌症）也与增加有关。