Abstract
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature |
| Vol/bind | 633 |
| Udgave nummer | 8030 |
| Sider (fra-til) | 608-614 |
| Antal sider | 7 |
| ISSN | 0028-0836 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:This work was funded by the Medical Research Council (Unit programmes: MC_UU_12015/2, MC_UU_00006/2, MC_UU_12015/1, and MC_UU_00006/1). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. This research was conducted using the UK Biobank Resource under application 9905 (University of Cambridge) and 9072 and 871 (University of Exeter). A full list of funding sources and acknowledgements can be found in the . This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.
Funding Information:
J.R.B.P. and E.J.G. are employees of Insmed Innovation UK and hold stock/stock options in Insmed. J.R.B.P. has also received consultancy fees from Hertility Health and WW International and holds research funding from GSK. The other authors declare no competing interests.
Publisher Copyright:
© The Author(s) 2024.