Genetic links between ovarian ageing, cancer risk and de novo mutation rates

Stasa Stankovic, Saleh Shekari, Qin Qin Huang, Eugene J. Gardner, Erna V. Ivarsdottir, Nick D. L. Owens, Nasim Mavaddat, Ajuna Azad, Gareth Hawkes, Katherine A. Kentistou, Robin N. Beaumont, Felix R. Day, Yajie Zhao, Hakon Jonsson, Thorunn Rafnar, Vinicius Tragante, Gardar Sveinbjornsson, Asmundur Oddsson, Unnur Styrkarsdottir, Julius Gudmundsson, Simon N. Stacey, Daniel F. Gudbjartsson, Kitale Kennedy, Andrew R. Wood, Michael N. Weedon, Ken K. Ong, Caroline F. Wright, Eva R. Hoffmann, Patrick Sulem, Matthew E. Hurles, Katherine S. Ruth, Hilary C. Martin, Kari Stefansson, John R. B. Perry () and Anna Murray ()
Additional contact information
Stasa Stankovic: University of Cambridge
Saleh Shekari: University of Exeter
Qin Qin Huang: Wellcome Genome Campus
Eugene J. Gardner: University of Cambridge
Erna V. Ivarsdottir: deCODE Genetics/Amgen
Nick D. L. Owens: University of Exeter
Nasim Mavaddat: University of Cambridge
Ajuna Azad: University of Copenhagen
Gareth Hawkes: University of Exeter
Katherine A. Kentistou: University of Cambridge
Robin N. Beaumont: University of Exeter
Felix R. Day: University of Cambridge
Yajie Zhao: University of Cambridge
Hakon Jonsson: deCODE Genetics/Amgen
Thorunn Rafnar: deCODE Genetics/Amgen
Vinicius Tragante: deCODE Genetics/Amgen
Gardar Sveinbjornsson: deCODE Genetics/Amgen
Asmundur Oddsson: deCODE Genetics/Amgen
Unnur Styrkarsdottir: deCODE Genetics/Amgen
Julius Gudmundsson: deCODE Genetics/Amgen
Simon N. Stacey: deCODE Genetics/Amgen
Daniel F. Gudbjartsson: deCODE Genetics/Amgen
Kitale Kennedy: University of Exeter
Andrew R. Wood: University of Exeter
Michael N. Weedon: University of Exeter
Ken K. Ong: University of Cambridge
Caroline F. Wright: University of Exeter
Eva R. Hoffmann: University of Copenhagen
Patrick Sulem: deCODE Genetics/Amgen
Matthew E. Hurles: Wellcome Genome Campus
Katherine S. Ruth: University of Exeter
Hilary C. Martin: Wellcome Genome Campus
Kari Stefansson: deCODE Genetics/Amgen
John R. B. Perry: University of Cambridge
Anna Murray: University of Exeter

Nature, 2024, vol. 633, issue 8030, 608-614

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07931-x

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