Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Academic Unit of Pathology Department of Neuroscience University of Sheffield Sheffield UK

Amsterdam Public Health Research Institute Amsterdam The Netherlands

Amsterdam Reproduction and Development Research Institute Amsterdam The Netherlands

Biobank of Eastern Finland Kuopio University Hospital Kuopio Finland

Biostatistics and Computational Biology Branch National Institute of Environmental Health Sciences NIH Research Triangle Park NC USA

Boston University School of Medicine Department of Medicine Section of General Internal Medicine Boston MA USA

Brigham and Women's Hospital Boston MA USA

Broad Institute of Harvard and MIT Cambridge MA USA

Cancer and Environment Group Center for Research in Epidemiology and Population Health INSERM University Paris Sud University Paris Saclay Villejuif France

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Epidemiology Group University Cancer Center Hamburg University Medical Center Hamburg Eppendorf Hamburg Germany

Cancer Research Institute Queen's University Kingston Ontario Canada

Cardiovascular Health Research Unit Departments of Medicine Epidemiology and Health Services University of Washington Seattle WA USA

Center for Human Genetics Division of Public Health Sciences Wake Forest School of Medicine Wake Forest NC USA

Central Hospital of Augsburg MONICA KORA Myocardial Infarction Registry Augsburg Germany

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Centre for Cardiovascular Sciences Queen's Medical Research Institute University of Edinburgh Royal Infirmary of Edinburgh Edinburgh UK

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Centre for Genomics and Personalised Health School of Biomedical Sciences Faculty of Health Queensland University of Technology Brisbane Queensland Australia

Centre for Global Health Research Usher Institute University of Edinburgh Edinburgh UK

Centro Andaluz de Biología Molecular y Medicina Regenerativa Universidad de Sevilla Universidad Pablo de Olavide Seville Spain

Chair of Genetic Epidemiology IBE Faculty of Medicine LMU Munich Munich Germany

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Clalit National Cancer Control Center Carmel Medical Center and Technion Faculty of Medicine Haifa Israel

Clinical Research Center Shizuoka General Hospital Shizuoka Japan

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

David Geffen School of Medicine Department of Medicine Division of Hematology and Oncology University of California at Los Angeles Los Angeles CA USA

Department of Applied Genetics School of Pharmaceutical Sciences University of Shizuoka Shizuoka Japan

Department of Biological Psychology Vrije Universiteit Amsterdam Amsterdam The Netherlands

Department of Biostatistics Boston University School of Public Health Boston MA USA

Department of Biostatistics Harvard T H Chan School of Public Health Boston MA USA

Department of Biostatistics University of Washington Seattle WA USA

Department of Cancer Epidemiology Clinical Sciences Lund University Lund Sweden

Department of Cell Biology Physiology and Immunology Universitat Autònoma de Barcelona Cerdanyola del Vallès Spain

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

Department of Clinical Epidemiology Leiden University Medical Center Leiden the Netherlands

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Pathology The University of Melbourne Melbourne Victoria Australia

Department of Computational Biology University of Lausanne Lausanne Switzerland

Department of Endocrinology University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Epidemiology and Population Health Stanford University School of Medicine Stanford CA USA

Department of Epidemiology Brown University Providence RI USA

Department of Epidemiology Erasmus MC Rotterdam The Netherlands

Department of Epidemiology Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Epidemiology Gillings School of Global Public Health University of North Carolina Chapel Hill NC USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA USA

Department of Epidemiology School of Public Health University of Michigan Ann Arbor MI USA

Department of Epidemiology University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Epidemiology University of Pittsburgh Pittsburgh PA USA

Department of Epidemiology University of Washington Seattle WA USA

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Department of Genetics University Medical Centre Utrecht Utrecht The Netherlands

Department of Gynecology and Obstetrics Comprehensive Cancer Center ER EMN University Hospital Erlangen Friedrich Alexander University Erlangen Nuremberg Erlangen Germany

Department of Health Science Research Division of Epidemiology Mayo Clinic Rochester MN USA

Department of Health Sciences Research Mayo Clinic Rochester MN USA

Department of Human Genetics Leiden University Medical Center Leiden the Netherlands

Department of Internal Medicine Division of Endocrinology Leiden University Medical Center Leiden the Netherlands

Department of Internal Medicine Erasmus MC Rotterdam The Netherlands

Department of Internal Medicine Section of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands

Department of Internal Medicine The Ohio State University Columbus OH USA

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Sciences University of Trieste Trieste Italy

Department of Medicine Brown University Providence RI USA

Department of Medicine Division of Oncology Stanford Cancer Institute Stanford University School of Medicine Stanford CA USA

Department of Medicine Internal Medicine Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Department of Medicine University of Pittsburgh Pittsburgh PA USA

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Nutrition Harvard T H Chan School of Public Health Boston MA USA

Department of Obstetrics and Gynaecology Campus Grosshadern Ludwig Maximilians Universität Munich Germany

Department of Obstetrics and Gynaecology University of Cambridge The Rosie Hospital and NIHR Cambridge Biomedical Research Centre Cambridge UK

Department of Obstetrics and Gynecology University Medicine Greifswald Greifswald Germany

Department of Oncology University Hospital of Larissa Larissa Greece

Department of Paediatrics University of Cambridge Cambridge UK

Department of Population Science American Cancer Society Atlanta GA USA

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Public Health and Primary Care Leiden University Medical Center Leiden the Netherlands

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Public Health Sciences Queen's University Kingston Ontario Canada

Department of Surgical Sciences Uppsala University Uppsala Sweden

Department of Twin Research and Genetic Epidemiology King's College London London UK

Division of Breast Cancer Research The Institute of Cancer Research London UK

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Department of Health and Human Services Bethesda MD USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Epidemiology and Community Health University of Minnesotta Minneapolis MN USA

Division of Genetics and Epidemiology The Institute of Cancer Research London UK

Division of Medical Oncology Department of Internal Medicine University of Kentucky College of Medicine Lexington KY USA

Division of Molecular Pathology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Division of Population and Health Genomics University of Dundee Dundee UK

Division of Psychosocial Research and Epidemiology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA

Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Erasmus University Medical Center Rotterdam The Netherlands

Division of Reproductive Sciences Cincinnati Children's Hospital Medical Center Cincinnati OH USA

DNRF Center for Chromosome Stability Department of Cellular and Molecular Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

eCODE genetics Amgen Reykjavik Iceland

Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden the Netherlands

Epidemiology Branch National Institute of Environmental Health Sciences NIH Research Triangle Park NC USA

Epidemiology Program University of Hawaii Cancer Center Honolulu HI USA

Estonian Genome Center Institute of Genomics University of Tartu Tartu Estonia

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Medicine School of Health Sciences University of Iceland Reykjavik Iceland

Faculty of Medicine University of Iceland Reykjavik Iceland

Faculty of Medicine University of Split Split Croatia

Faculty of Science Charles University Prague Czech Republic

Fred A Litwin Center for Cancer Genetics Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada

Fundación Pública Galega de Medicina Xenómica Instituto de Investigación Sanitaria de Santiago de Compostela Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela Spain

Gen Info Ltd Zagreb Croatia

Genetics of Common Disorders Unit IRCCS San Raffaele Scientific Institute Milan Italy

Genetics of Human Complex Traits University of Exeter Medical School University of Exeter Exeter UK

Genome Integrity and Instability Group Institut de Biotecnologia i Biomedicina Universitat Autònoma de Barcelona Cerdanyola del Vallès Spain

Geriatric Unit Azienda Sanitaria Firenze Florence Italy

German Center for Diabetes Research Neuherberg Germany

Harvard Medical School Boston MA USA

Hebrew SeniorLife Institute for Aging Research Boston MA USA

Human Genetics Center School of Public Health The University of Texas Health Science Center at Houston Houston TX USA

Icelandic Heart Association Kopavogur Iceland

Institute for Community Medicine University Medicine Greifswald Greifswald Germany

Institute for Maternal and Child Health IRCCS 'Burlo Garofolo' Trieste Italy

Institute for Molecular Bioscience The University of Queensland Brisbane Queensland Australia

Institute of Animal Physiology and Genetics of the Czech Academy of Sciences Libechov Czech Republic

Institute of Clinical Medicine Pathology and Forensic Medicine University of Eastern Finland Kuopio Finland

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Epidemiology 2 Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Genetic Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Genetics and Biomedical Research National Research Council Cagliari Italy

Institute of Genetics and Biophysics CNR Naples Italy

Institute of Human Genetics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Medical Biometry and Epidemiology University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Medical Biostatistics Epidemiology and Informatics University Medical Center Johannes Gutenberg University Mainz Germany

Interfaculty Institute for Genetics and Functional Genomics University Medicine Greifswald Greifswald Germany

IRCCS Neuromed Pozzilli Isernia Italy

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht University Utrecht the Netherlands

Karolinska Institutet Department of Medical Epidemiology and Biostatistics Stockholm Sweden

Laboratory for Genomics of Diabetes and Metabolism RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory for Statistical and Translational Genetics RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory Medicine Program University Health Network Toronto Ontario Canada

Laboratory of Epidemiology and Population Sciences National Institute on Aging Intramural Research Program National Institutes of Health Bethesda MD USA

Laboratory of Neurogenetics National Institute on Aging National Institutes of Health Bethesda MD USA

Laboratory of Reproductive Biology The Juliane Marie Centre for Women Children and Reproduction Copenhagen University Hospital and Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Me Inc Sunnyvale CA USA

Medical Genetics Section Centre for Genomic and Experimental Medicine Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh UK

Moores Cancer Center University of California San Diego La Jolla CA USA

MRC Biostatistics Unit University of Cambridge Cambridge UK

MRC Epidemiology Unit University of Cambridge School of Clinical Medicine Institute of Metabolic Science Cambridge Biomedical Campus Cambridge UK

MRC Human Genetics Unit Institute of Genetics and Molecular Medicine University of Edinburgh Western General Hospital Edinburgh UK

MRC Integrative Epidemiology Unit University of Bristol Bristol UK

MRC Population Health Research Unit University of Oxford Oxford UK

National Institute on Aging Intramural Research Program Baltimore MD USA

NHLBI's and Boston University's Framingham Heart Study Framingham MA USA

NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust London UK

Nuffield Department of Population Health University of Oxford Oxford UK

Oncode Institute Utrecht The Netherlands

Oncology and Genetics Unit Instituto de Investigacion Sanitaria Galicia Sur Xerencia de Xestion Integrada de Vigo SERGAS Vigo Spain

Peking University Center for Public Health and Epidemic Preparedness and Response Beijing P R China

Population and Medical Genetics Broad Institute Cambridge MA USA

Population Health Science Bristol Medical School University of Bristol Bristol UK

Population Oncology BC Cancer Vancouver British Columbia Canada

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

QIMR Berghofer Medical Research Insititute Brisbane Queensland Australia

Quantify Research Stockholm Sweden

Radiation Epidemiology Branch Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Reproductive Medicine Department of Obstetrics and Gynaecology Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

Research Unit of Molecular Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

School of Cancer and Pharmaceutical Sciences Comprehensive Cancer Centre Guy's Campus King's College London London UK

School of Life Sciences University of Westminster London UK

School of Population and Public Health University of British Columbia Vancouver BC Canada

School of Public Health Peking University Health Science Center Beijing P R China

Sheffield Institute for Nucleic Acids Department of Oncology and Metabolism University of Sheffield Sheffield UK

Structural and Computational Biology Unit EMBL Heidelberg Germany

Survey Research Center Institute for Social Research Ann Arbor MI USA

Swiss Institute of Bioinformatics Lausanne Switzerland

The Cancer Prevention and Control Research Program University of Kentucky Markey Cancer Center Lexington KY USA

The Institute of Medical Sciences Aberdeen Biomedical Imaging Centre University of Aberdeen Aberdeen UK

The Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

The Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Transgenic Animal Unit Center of Animal Biotechnology and Gene Therapy Universitat Autònoma de Barcelona Cerdanyola del Vallès Spain

Transgenic Core Facility Department of Experimental Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Translational Cancer Research Area University of Eastern Finland Kuopio Finland

Translational Gerontology Branch National Institute on Aging Baltimore MD USA

University Center for Primary Care and Public Health University of Lausanne Lausanne Switzerland

University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit Wellcome MRC Institute of Metabolic Science Addenbrooke's Hospital Cambridge UK

University of Groningen University Medical Center Groningen Department of Genetics Groningen The Netherlands

University of Sassari Department of Biomedical Sciences Sassari Italy

Women's Health Initiative Branch National Heart Lung and Blood Institute Bethesda MD USA

Komentář v

Nature. 2021 Aug;596(7872):345-346. doi: 10.1038/d41586-021-01710-8. PubMed

Komentář v

Nat Rev Endocrinol. 2021 Oct;17(10):575. doi: 10.1038/s41574-021-00558-2. PubMed

Komentář v

Nat Rev Genet. 2021 Oct;22(10):623. doi: 10.1038/s41576-021-00415-y. PubMed

Zobrazit více v PubMed

Lambalk CB, van Disseldorp J, de Koning CH, Broekmans FJ. Testing ovarian reserve to predict age at menopause. Maturitas. 2009;63:280–91. PubMed

Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet (London, England) 2019;394:1159–1168. PubMed PMC

Murray A, et al. Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency. Genet Med. 2014;16:19–24. PubMed PMC

Christensen K, Doblhammer G, Rau R, Vaupel JW. Ageing populations: the challenges ahead. Lancet (London, England) 2009;374:1196–208. PubMed PMC

InterLACE Study Team. Variations in reproductive events across life: a pooled analysis of data from 505 147 women across 10 countries. Hum Reprod. 2019;34:881–893. PubMed PMC

Gruhn JR, et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science. 2019;365:1466–1469. PubMed PMC

Donnez J, Dolmans M-M. Fertility Preservation in Women. N Engl J Med. 2017;377:1657–1665. PubMed

Yding Andersen C, Mamsen LS, Kristensen SG. FERTILITY PRESERVATION: Freezing of ovarian tissue and clinical opportunities. Reproduction. 2019;158:F27–F34. PubMed

Argyle CE, Harper JC, Davies MC. Oocyte cryopreservation: where are we now? Hum Reprod Update. 2016;22:440–9. PubMed

Stolk L, et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet. 2012;44:260–8. PubMed PMC

Venturella R, et al. The Genetics of Non-Syndromic Primary Ovarian Insufficiency: A Systematic Review. Int J Fertil Steril. 2019;13:161–168. PubMed PMC

Titus S, et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5:172ra21 PubMed PMC

Day FR, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet. 2015;47:1294–303. PubMed PMC

Horikoshi M, et al. Elucidating the genetic architecture of reproductive ageing in the Japanese population. Nat Commun. 2018;9:1977. PubMed PMC

Caburet S, et al. Homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anaemia trait. J Med Genet. 2020 doi: 10.1136/jmedgenet-2019-106672. PubMed DOI

Thompson DJ, et al. Genetic predisposition to mosaic Y chromosome loss in blood. Nature. 2019;575:652–657. PubMed PMC

Day FR, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet. 2017;10:1–19. PubMed PMC

Boyle EA, Li YI, Pritchard JK. An Expanded View of Complex Traits: From Polygenic to Omnigenic. Cell. 2017;169:1177–1186. PubMed PMC

Reddy P, et al. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science. 2008;319:611–3. PubMed

Suh E-K, et al. p63 protects the female germ line during meiotic arrest. Nature. 2006;444:624–8. PubMed

Deutsch GB, et al. DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer. Cell. 2011;144:566–76. PubMed PMC

Tuppi M, et al. Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63. Nat Struct Mol Biol. 2018;25:261–269. PubMed

Rinaldi VD, Bloom JC, Schimenti JC. Oocyte Elimination Through DNA Damage Signaling from CHK1/CHK2 to p53 and p63. Genetics. 2020;215:373–378. PubMed PMC

Aiken CE, Tarry-Adkins JL, Penfold NC, Dearden L, Ozanne SE. Decreased ovarian reserve, dysregulation of mitochondrial biogenesis, and increased lipid peroxidation in female mouse offspring exposed to an obesogenic maternal diet. FASEB J. 2016;30:1548–56. PubMed PMC

Pittman DL, et al. Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol Cell. 1998;1:697–705. PubMed

Nakajo N, et al. Absence of Wee1 ensures the meiotic cell cycle in Xenopus oocytes. Genes Dev. 2000;14:328–38. PubMed PMC

Ruth KS, et al. Events in Early Life are Associated with Female Reproductive Ageing: A UK Biobank Study. Sci Rep. 2016;6:24710. PubMed PMC

Bolcun-Filas E, Rinaldi VD, White ME, Schimenti JC. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science. 2014;343:533–536. PubMed PMC

Adhikari D, et al. Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan. Cell Res. 2016;26:1212–1225. PubMed PMC

Rinaldi VD, Bolcun-Filas E, Kogo H, Kurahashi H, Schimenti JC. The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure. Mol Cell. 2017;67:1026–1036.:e2. PubMed PMC

Tharp ME, Malki S, Bortvin A. Maximizing the ovarian reserve in mice by evading LINE-1 genotoxicity. Nat Commun. 2020;11:330. PubMed PMC

Liu Q, et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000;14:1448–59. PubMed PMC

Abe H, et al. CHEK1 coordinates DNA damage signaling and meiotic progression in the male germline of mice. Hum Mol Genet. 2018;27:1136–1149. PubMed PMC

Chen L, et al. Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes. Cell Cycle. 2012;11:1948–55. PubMed

Pacheco S, et al. ATR is required to complete meiotic recombination in mice. Nat Commun. 2018;9:2622. PubMed PMC

Pacheco S, Maldonado-Linares A, Garcia-Caldés M, Roig I. ATR function is indispensable to allow proper mammalian follicle development. Chromosoma. 2019;128:489–500. PubMed

López-Contreras AJ, Gutierrez-Martinez P, Specks J, Rodrigo-Perez S, Fernandez-Capetillo O. An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation. J Exp Med. 2012;209:455–61. PubMed PMC

Salpeter SR, et al. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab. 2006;8:538–54. PubMed

Manson JE, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310:1353–68. PubMed PMC

Ruth KS, et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med. 2020;26:252–258. PubMed PMC

Dam V, et al. Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis. Int J Epidemiol. 2019;48:1275–1285. PubMed PMC

de Kat AC, et al. Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study. BMC Med. 2017;15:2. PubMed PMC

Atsma F, Bartelink M-LEL, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause. 13:265–79. PubMed

Ambikairajah A, Walsh E, Cherbuin N. Lipid profile differences during menopause: a review with meta-analysis. Menopause. 2019;26:1327–1333. PubMed

Pike CJ. Sex and the development of Alzheimer’s disease. J Neurosci Res. 2017;95:671–680. PubMed PMC

Zhu D, et al. Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies. Eur J Epidemiol. 2018;33:699–710. PubMed

Shadyab AH, et al. Ages at menarche and menopause and reproductive lifespan as predictors of exceptional longevity in women: the Women’s Health Initiative. Menopause. 2017;24:35–44. PubMed PMC

Bycroft C, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203–209. PubMed PMC

Tyrrell J, et al. Using genetics to understand the causal influence of higher BMI on depression. Int J Epidemiol. 2019;48:834–848. PubMed PMC

Loh P-R, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47:284–290. PubMed PMC

Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011;88:76–82. PubMed PMC

Terao C, et al. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature. 2020;584:130–135. PubMed PMC

Wood AR, et al. Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively. Diabetologia. 2016;59:1214–21. PubMed PMC

Szustakowski JD, et al. Advancing Human Genetics Research and Drug Discovery through Exome Sequencing of the UK Biobank. medRxiv. 2020:2020.11.02.20222232. doi: 10.1101/2020.11.02.20222232. PubMed DOI

McLaren W, et al. The Ensembl Variant Effect Predictor. Genome Biol. 2016;17:122. PubMed PMC

Zhou W, et al. Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts. Nat Genet. 2020;52:634–639. PubMed PMC

Zhu Z, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016;48:481–487. PubMed

Pers TH, et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat Commun. 2015;6:5890. PubMed PMC

Tabula Muris Consortium et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018;562:367–372. PubMed PMC

Nestorowa S, et al. A single-cell resolution map of mouse hematopoietic stem and progenitor cell differentiation. Blood. 2016;128:e20–31. PubMed PMC

Finucane HK, et al. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat Genet. 2018;50:621–629. PubMed PMC

GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60. PubMed PMC

Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–30. PubMed PMC

Fehrmann RSN, et al. Gene expression analysis identifies global gene dosage sensitivity in cancer. Nat Genet. 2015;47:115–25. PubMed

Segrè AV, et al. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 2010;6 PubMed PMC

de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: Generalized Gene-Set Analysis of GWAS Data. PLoS Comput Biol. 2015;11 PubMed PMC

Lamparter D, Marbach D, Rueedi R, Kutalik Z, Bergmann S. Fast and Rigorous Computation of Gene and Pathway Scores from SNP-Based Summary Statistics. PLoS Comput Biol. 2016;12:e1004714. PubMed PMC

Deelen P, et al. Improving the diagnostic yield of exome- sequencing by predicting gene-phenotype associations using large-scale gene expression analysis. Nat Commun. 2019;10:2837. PubMed PMC

Knijnenburg TA, et al. Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep. 2018;23:239–254.:e6. PubMed PMC

Pearl LH, Schierz AC, Ward SE, Al-Lazikani B, Pearl FMG. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer. 2015;15:166–80. PubMed

Álvarez-Quilón A, et al. Endogenous DNA 3’ Blocks Are Vulnerabilities for BRCA1 and BRCA2 Deficiency and Are Reversed by the APE2 Nuclease. Mol Cell. 2020;78:1152–1165.:e8. PubMed PMC

Vilhjálmsson BJ, et al. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores. Am J Hum Genet. 2015;97:576–92. PubMed PMC

Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. PubMed PMC

Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37:658–65. PubMed PMC

Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32:377–389. PubMed PMC

Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40:304–14. PubMed PMC

Bowden J, et al. Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. Int J Epidemiol. 2018;47:2100. PubMed PMC

Samuelsson A-M, et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertens (Dallas,Tex 1979) 2008;51:383–92. PubMed

Sankar A, et al. KDM4A regulates the maternal-to-zygotic transition by protecting broad H3K4me3 domains from H3K9me3 invasion in oocytes. Nat Cell Biol. 2020;22:380–388. PubMed PMC

Li L, et al. Single-Cell RNA-Seq Analysis Maps Development of Human Germline Cells and Gonadal Niche Interactions. Cell Stem Cell. 2017;20:858–873.:e4. PubMed

Zhang Y, et al. Transcriptome Landscape of Human Folliculogenesis Reveals Oocyte and Granulosa Cell Interactions. Mol Cell. 2018;72:1021–1034.:e4. PubMed

Bolger AM, Lohse M, Usadel B. Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–2120. PubMed PMC

Chen S, et al. AfterQC: automatic filtering, trimming, error removing and quality control for fastq data. BMC Bioinformatics. 2017;18:80. PubMed PMC

Li H, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–2079. PubMed PMC

Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc. 2016;11:1650–67. PubMed PMC

Takai H, et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 2002;21:5195–205. PubMed PMC

Lewandoski M, Wassarman KM, Martin GR. Zp3-cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line. Curr Biol. 1997;7:148–51. PubMed

Lam MH, Liu Q, Elledge SJ, Rosen JM. Chk1 is haploinsufficient for multiple functions critical to tumor suppression. Cancer Cell. 2004;6:45–59. PubMed

Takeo T, Nakagata N. Superovulation using the combined administration of inhibin antiserum and equine chorionic gonadotropin increases the number of ovulated oocytes in C57BL/6 female mice. PLoS One. 2015;10:e0128330. PubMed PMC

Schindelin J, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82. PubMed PMC

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer

Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE

CHK1-CDC25A-CDK1 regulate cell cycle progression and protect genome integrity in early mouse embryos