Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing¹. Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility¹, with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan—that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk.

对常见变异的人类遗传学研究为控制卵巢衰老的生物学机制提供了实质性的见解¹。在这里，我们报告了对来自英国生物样本库研究的 106,973 名女性的罕见蛋白质编码变异的分析，这些基因的影响比以前发现的常见变异（ETAA1、ZNF518A、PNPLA8、PALB2 和 SAMHD1）大五倍左右。SAMHD1 关联加强了卵巢衰老与癌症易感性之间的联系¹，破坏性种系变异与男性和女性的生殖寿命延长和全因癌症风险增加有关。ZNF518A 中的蛋白质截短变异与较短的生殖寿命相关，即绝经年龄较早 （5.61 岁） 和月经初潮年龄较晚 （0.56 岁）。最后，使用来自 100,000 个基因组计划 （100kGP） 的 8,089 个测序三重奏，我们观察到与早期卵巢衰老相关的常见遗传变异与母源性从头突变率的增加有关。尽管我们无法在 deCODE 研究的独立样本中复制这一发现，但它与 DNA 损伤反应基因在维持生殖细胞遗传完整性方面的预期作用一致。这项研究提供了更年期年龄与癌症风险之间遗传联系的证据。