ESPE Yearbook of Paediatric Endocrinology

Nature. 2024 Sep;633(8030):608-614. doi: 10.1038/s41586-024-07931-x. PMID: 39261734.

Brief summary: This study analysed UK Biobank data to expand current knowledge on the genetic architecture of ovarian ageing. It identified a shared genetic mechanism linking the start and end of female reproductive life, with ZNF518A emerging as a key regulator of both puberty timing and ovarian ageing.

Ovarian ageing, marked by age at natural menopause (ANM), impacts fertility and long-term health (1). While common genetic variants have been linked to ANM, the role of rare protein-coding variants was less explored (1). This study investigated rare damaging variants in over 100,000 women from the UK Biobank to uncover novel genetic contributors to ovarian ageing and their broader implications.

The study identified 9 genes associated with ANM, including 5 novel ones: ETAA1, ZNF518A, PNPLA8, PALB2, and SAMHD1. Notably, protein-truncating variants (PTVs) in ZNF518A led to shorter reproductive lifespan with earlier menopause (5.6 years) and later age at menarche (0.56 years), while damaging variants in SAMHD1 delayed menopause by 1.35 years. Several of these genes are involved in DNA damage repair, reinforcing the link between genomic integrity and reproductive lifespan. Additionally, SAMHD1 variants were associated with increased cancer risk in both sexes, particularly hormone-sensitive cancers.

Using data from the 100,000 Genomes Project, the authors also found that genetic predisposition to earlier menopause correlates with higher rates of maternally derived de novo mutations (DNMs) in offspring, although this was not replicated in the deCODE cohort.

This study expands the genetic architecture of ovarian ageing by identifying rare coding variants with large effects on ANM. It highlights the dual role of DNA damage repair genes in reproductive ageing and cancer susceptibility and suggests a potential intergenerational impact via increased DNMs. These findings offer new insights into the biology of reproductive ageing and its broader health consequences, with implications for fertility treatment and cancer risk assessment.

Reference: 1. Ruth KS et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021 Aug;596(7872):393-397. doi: 10.1038/s41586-021-03779-7. Epub 2021 Aug 4. PMID: 34349265; PMCID: PMC7611832.