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

• 成果类型: Article
• 署名作者: Stankovic, Stasa; Shekari, Saleh; Huang, Qin Qin; Gardner, Eugene J.; Ivarsdottir, Erna V.; Owens, Nick D. L.; Mavaddat, Nasim; Azad, Ajuna; Hawkes, Gareth; Kentistou, Katherine A.; Beaumont, Robin N.; Day, Felix R.; Zhao, Yajie; Jonsson, Hakon; Rafnar, Thorunn; Tragante, Vinicius; Sveinbjornsson, Gardar; Oddsson, Asmundur; Styrkarsdottir, Unnur; Gudmundsson, Julius; Stacey, Simon N.; Gudbjartsson, Daniel F.; Kennedy, Kitale; Wood, Andrew R.; Weedon, Michael N.; Ong, Ken K.; Wright, Caroline F.; Hoffmann, Eva R.; Sulem, Patrick; Hurles, Matthew E.; Ruth, Katherine S.; Martin, Hilary C.; Stefansson, Kari; Perry, John R. B.; Murray, Anna
• 署名单位: University of Cambridge; University of Exeter; University of Queensland; Wellcome Trust Sanger Institute; Decode Genetics; University of Cambridge; University of Copenhagen; University of Cambridge; University of Cambridge
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4580
• DOI: 10.1038/s41586-024-07931-x
• 发表日期: 2024-09-19
• 页码: 608-614
• 关键词: genome-wide association; mendelian randomization; dna-repair; maximum-likelihood; function variants; early menopause; cell-cycle; samhd1; AGE; instruments

摘要

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. Analyses focusing on protein-truncating variants from 106,973 women from in the UK Biobank identify variants in genes that reinforce the link between reproductive lifespan in women and cancer risk in both sexes.