Nature

, volume 596 , issue 7872 , pages 393-397

Genetic insights into biological mechanisms governing human ovarian ageing

Katherine S. Ruth ¹

Felix R. Day ²

Jazib Hussain ³

Ana Martínez Marchal ^{4, 5}

Catherine E. Aiken ^{6, 7}

Ajuna Azad ³

Deborah J. Thompson ⁸

Lucie Knoblochova ^{9, 10}

Hironori Abe ¹¹

Jane L. Tarry-Adkins ^{6, 7}

Javier Martin Gonzalez ¹²

Pierre Fontanillas ¹³

Annique Claringbould ¹⁴

Olivier B Bakker ¹⁵

Patrick Sulem ¹⁶

Robin G. Walters ^{17, 18}

Chikashi Terao ^{19, 20, 21}

Sandra Turon ²²

Momoko Horikoshi ²³

Kuang Lin ¹⁷

N. Charlotte Onland-Moret ²⁴

Aditya Sankar ³

Emil Peter Thrane Hertz ^{3, 25}

Pascal N Timshel ²⁶

Vallari Shukla ³

Rehannah Borup ³

Kristina W Olsen ^{3, 27}

Paula Aguilera ^{3, 28}

Mònica Ferrer Roda ^{4, 5}

Yan Huang ^{4, 5}

Stasa Stankovic ²

Paul R H J Timmers ^{29, 30}

Thomas U. Ahearn ³¹

Behrooz Z. Alizadeh ³²

Elnaz Naderi ³²

Irene L. Andrulis ^{33, 34}

Alice M Arnold ³⁵

Kristan J Aronson ^{36, 37}

Annelie Augustinsson ³⁸

Stefania Bandinelli ³⁹

Caterina M Barbieri ⁴⁰

Robin N Beaumont ¹

Heiko Becher ⁴¹

Matthias W. Beckmann ⁴²

Stefania Benónísdóttir ¹⁶

Sven Bergmann ^{43, 44}

Murielle Bochud ⁴⁵

Eric Boerwinkle ⁴⁶

Stig E. Bojesen ^{47, 48, 49}

Manjeet K. Bolla ⁸

Dorret I. Boomsma ^{50, 51, 52}

Nicholas Bowker ²

Jennifer A. Brody ⁵³

Linda Broer ⁵⁴

Julie E. Buring ^{55, 56}

Archie Campbell ⁵⁷

Harry Campbell ²⁹

Jose E. Castelao ⁵⁸

Eulalia Catamo ⁵⁹

Stephen J. Chanock ³¹

Georgia Chenevix-Trench ⁶⁰

Marina Ciullo ^{61, 62}

Tanguy Corre ^{43, 44, 45}

Fergus J Couch ⁶³

Angela Cox ⁶⁴

Laura Crisponi ⁶⁵

Simon S Cross ⁶⁶

Francesco Cucca ^{65, 67}

Kamila Czene ⁶⁸

George Davey Smith ^{69, 70}

Eco J C N De Geus ^{50, 51, 52}

Renée de Mutsert ⁷¹

Immaculata De Vivo ^{72, 73}

Ellen W Demerath ⁷⁴

Joe Dennis ⁸

Alison M. Dunning ⁷⁵

Miriam Dwek ⁷⁶

Mikael Eriksson ⁷⁷

Tonu Esko ^{78, 79}

Peter A. Fasching ^{42, 80}

Jessica D. Faul ⁸¹

Luigi Ferrucci ⁸²

Nora Franceschini ⁸³

Timothy M. Frayling ¹

Manuela Gago-Dominguez ^{84, 85}

Massimo Mezzavilla ⁸⁶

Montserrat García-Closas ³¹

Christian Gieger ^{87, 88, 89}

Graham G. Giles ^{90, 91, 92}

Harald Grallert ^{87, 88, 89}

Daniel F. Gudbjartsson ¹⁶

Vilmundur Gudnason ^{93, 94}

Guénel Pascal ⁹⁵

Christopher A. Haiman ⁹⁶

Niclas Håkansson ⁹⁷

Per Hall ⁶⁸

Caroline Hayward ³⁰

Chunyan He ^{98, 99}

Wei He ⁷⁷

Gerardo Heiss ⁸³

Miya K Høffding ³

John L. Hopper ⁹¹

Jouke J. Hottenga ^{50, 51, 52}

Frank Hu ^{72, 73, 100}

David Hunter ^{17, 72, 73, 100, 101}

Mohammad A Ikram ¹⁰²

Rebecca D Jackson ¹⁰³

Micaella D R Joaquim ¹

Esther M. John ^{104, 105}

Peter K Joshi ²⁹

DAVID KARASIK ^{56, 106}

Sharon L. R. Kardia ¹⁰⁷

Christiana Kartsonaki ^{17, 18}

Robert Karlsson ⁷⁷

Cari M. Kitahara ¹⁰⁸

Ivana Kolcic ¹⁰⁹

Charles Kooperberg ¹¹⁰

Peter Kraft ^{72, 111}

Allison W. Kurian ^{104, 105}

Zoltán Kutalik ^{44, 45}

Martina La Bianca ⁵⁹

Geneviève Lachance ¹¹²

Claudia Langenberg ²

Lenore J. Launer ¹¹³

Joop S.E. Laven ¹¹⁴

Deborah A. Lawlor ^{69, 70}

Loïc Le Marchand ¹¹⁵

Jingmei Li ⁶⁸

Annika Lindblom ^{116, 117}

Sara Lindström ¹¹⁸

Tricia Lindstrom ¹¹⁹

Martha Linet ¹⁰⁸

Yongmei Liu ¹²⁰

Simin Liu ^{121, 122}

Jian'an Luan ²

Reedik Mägi ⁷⁹

Patrik K.E. Magnusson ⁷⁷

Massimo Mangino ^{112, 123}

Mannermaa Arto ^{124, 125, 126}

Marco Brumat ⁸⁶

Jonathan Marten ³⁰

Nicholas G. Martin ¹²⁷

Hamdi Mbarek ^{50, 51, 52}

Barbara McKnight ³⁵

Sarah E. Medland ¹²⁷

Christa Meisinger ^{88, 128}

Thomas Meitinger ¹²⁹

Cristina Menni ¹¹²

Andres Metspalu ⁷⁹

Lili Milani ⁷⁹

Roger L. Milne ^{90, 91, 92}

Grant W. Montgomery ¹³⁰

Dennis O. Mook-Kanamori ^{71, 131}

Antonella Mulas ⁶⁵

Anna M. Mulligan ^{132, 133}

Alison Murray ¹³⁴

Mike A Nalls ¹³⁵

Anne Newman ^{136, 137}

Raymond Noordam ¹³⁸

Teresa Nutile ⁶¹

Dale R. Nyholt ¹³⁹

Andrew F. Olshan ¹⁴⁰

Hakan Olsson ³⁸

Jodie N. Painter ¹²⁷

Alpa V. Patel ¹⁴¹

Nancy L Pedersen ⁷⁷

Natalia Perjakova ⁷⁹

Annette Peters ^{88, 89}

Ulrike Peters ¹¹⁰

Paul D. P. Pharoah ^{8, 75}

Ozren Polašek ^{109, 142}

Eleonora Porcu ⁶⁵

Bruce M. Psaty ⁵³

Iffat Rahman ¹⁴³

Gad Rennert ¹⁴⁴

Hedy S. Rennert ¹⁴⁴

Paul M Ridker ^{55, 56}

Susan M Ring ^{69, 70}

Antonietta Robino ⁵⁹

Lynda M. Rose ⁵⁵

Frits R. Rosendaal ⁷¹

Jacques Rossouw ¹⁴⁵

Igor Rudan ²⁹

Rico Rueedi ^{43, 44}

Daniela Ruggiero ^{61, 62}

Cinzia F Sala ⁴⁰

Emmanouil Saloustros ¹⁴⁶

Dale P. Sandler ¹⁴⁷

Serena Sanna ⁶⁵

Elinor J. Sawyer ¹⁴⁸

Chloé Sarnowski ¹⁴⁹

David Schlessinger ¹⁵⁰

Marjanka K. Schmidt ^{151, 152}

Minouk J. Schoemaker ¹⁵³

Katharina E. Schraut ^{29, 154}

Christopher Scott ¹¹⁹

Saleh Shekari ¹

Amruta Shrikhande ³

Albert V. Smith ^{93, 94}

Blair H. Smith ¹⁵⁵

Jennifer A Smith ¹⁰⁷

Rossella Sorice ⁶¹

Melissa C. Southey ^{90, 92, 156}

Tim D. Spector ¹¹²

John J. Spinelli ^{157, 158}

Meir Stampfer ^{72, 73, 100}

Doris Stöckl ^{88, 159}

Joyce B.J. van Meurs ⁵⁴

Konstantin Strauch ^{160, 161, 162}

Unnur Styrkarsdottir ¹⁶

Anthony J. Swerdlow ^{153, 163}

Toshiko Tanaka ⁸²

Lauren R. Teras ¹⁴¹

Alexander Teumer ¹⁶⁴

Unnur þorsteinsdóttir ^{16, 165}

Nicholas J. Timpson ^{69, 70}

Daniela Toniolo ⁴⁰

Michela Traglia ⁴⁰

Melissa A. Troester ¹⁴⁰

Thérèse Truong ⁹⁵

Jessica Tyrrell ¹

Andre G. Uitterlinden ^{54, 102}

Sheila Ulivi ⁵⁹

Celine M Vachon ¹⁶⁶

Veronique Vitart ³⁰

Uwe Völker ¹⁶⁷

Peter Vollenweider ¹⁶⁸

Henry Völzke ¹⁶⁴

Qin Wang ⁸

Nicholas J Wareham ²

Clarice R. Weinberg ¹⁶⁹

David R Weir ⁸¹

Amber N Wilcox ³¹

Ko Willems van Dijk ^{170, 171, 172}

Gonneke Willemsen ^{50, 51, 52}

James F. Wilson ^{29, 30}

Bruce H. R. Wolffenbuttel ¹⁷³

Alicja Wolk ^{97, 174}

Andrew R. Wood ¹

Wei Zhao ¹⁰⁷

Marek Zygmunt ¹⁷⁵

Zhengming Chen ^{17, 18}

Liming Li ^{176, 177}

Lude Franke ^{15, 178}

Stephen Burgess ^{179, 180}

Patrick Deelen ^{15, 181}

Tune H. Pers ²⁶

Marie Louise Grøndahl ²⁷

Claus Yding Andersen ¹⁸²

Anna Pujol ²²

Andres J Lopez Contreras ^{3, 28}

Jeremy A. Daniel ²⁵

Kari Stefansson ^{16, 165}

Jenny Chang-Claude ^{183, 184}

Yvonne T van der Schouw ²⁴

Kathryn L. Lunetta ^{149, 185}

Daniel I. Chasman ^{55, 56}

Douglas F. Easton ^{8, 75}

Jenny A. Visser ⁵⁴

Susan E. Ozanne ⁶

Satoshi H. Namekawa ¹¹

Petr Solc ⁹

Joanne M. Murabito ^{185, 186}

Ken K. Ong ^{2, 187}

E. R. Hoffmann ³

Anna K Murray ¹

Ignasi Roig ^{4, 5}

John Perry ^{2, 54}

Hide authors affiliations Show authors affiliations: 187 affiliations

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

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

University of Cambridge

NIHR Cambridge Biomedical Research Centre

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

⁴

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

⁵

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

⁶

University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome–MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK |

⁷

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

University of Cambridge

NIHR Cambridge Biomedical Research Centre

⁸

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

⁹

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

¹⁰

Faculty of Science, Charles University, Prague, Czech Republic |

¹¹

Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA |

¹²

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

¹³

23andMe Inc., Sunnyvale, USA |

¹⁴

Structural and Computational Biology unit, EMBL, Heidelberg, Germany |

¹⁵

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

¹⁶

deCODE genetics/AMGEN, Reykjavik, Iceland |

¹⁷

Nuffield Department of Population Health, University of Oxford, Oxford, UK |

¹⁸

MRC Population Health Research Unit, University of Oxford, Oxford, UK |

¹⁹

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

²⁰

Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan |

²¹

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

²²

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

²³

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

²⁴

Julius Center for Health Sciences and Primary care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands |

²⁵

The Novo Nordisk Foundation Center for Protein Research, Faculty of health and medical sciences, University of Copenhagen, Copenhagen, Denmark

University of Copenhagen

Novo Nordisk

²⁶

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

University of Copenhagen

Novo Nordisk

²⁷

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

²⁸

Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC) – Universidad de Sevilla –Universidad Pablo de Olavide, Seville, Spain

Pablo de Olavide University

Andalusian Molecular Biology and Regenerative Medicine Center

²⁹

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

³⁰

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

³¹

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

³²

Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands |

³³

Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada |

³⁴

Department of Molecular Genetics, University of Toronto, Toronto, Canada |

³⁵

Department of Biostatistics, University of Washington, Seattle, USA |

³⁶

Department of Public Health Sciences, Queen’s University, Kingston, Canada |

³⁷

Cancer Research Institute, Queen’s University, Kingston, Canada |

³⁸

Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden |

³⁹

Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy |

⁴⁰

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

⁴¹

Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany |

⁴²

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

⁴³

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland |

⁴⁴

Swiss Institute of Bioinformatics, Lausanne, Switzerland |

⁴⁵

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

⁴⁶

Human Genetics Center, School of Public Health, The University of Texas Health Science Center At Houston, Houston, USA |

⁴⁷

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

⁴⁸

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

⁴⁹

Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark |

⁵⁰

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands |

⁵¹

Amsterdam Public Health (APH) Research Institute, Amsterdam, The Netherlands |

⁵²

Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam, The Netherlands |

⁵³

Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health services, University of Washington, Seattle, USA |

⁵⁴

Department of internal medicine, Erasmus MC, Rotterdam, the Netherlands |

⁵⁵

Brigham and Women’s Hospital, Boston, USA |

⁵⁶

HARVARD Medical school, Boston, USA |

⁵⁷

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

⁵⁸

Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain |

⁵⁹

Institute for Maternal and Child Health – IRCCS ‘Burlo Garofolo’, Trieste, Italy

Istituti di Ricovero e Cura a Carattere Scientifico

Children's hospital "Burlo Garofolo"

⁶⁰

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

⁶¹

Institute of Genetics and Biophysics – CNR, Naples, Italy |

⁶²

IRCCS Neuromed, Pozzilli, Isernia, Italy |

⁶³

Department of laboratory medicine and pathology, Mayo Clinic, Rochester, USA |

⁶⁴

Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK |

⁶⁵

Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy |

⁶⁶

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

⁶⁷

University of Sassari, Department of Biomedical Sciences, Sassari, Italy |

⁶⁸

Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden |

⁶⁹

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK |

⁷⁰

Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK |

⁷¹

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands |

⁷²

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, USA |

⁷³

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

Harvard University

Brigham and Women's Hospital

⁷⁴

Division of Epidemiology & Community Health, University of Minnesotta, Minneapolis, USA |

⁷⁵

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

⁷⁶

School of Life Sciences, University of Westminster, London, UK |

⁷⁷

Department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, Sweden |

⁷⁸

Population and Medical Genetics, Broad Institute, Cambridge, USA |

⁷⁹

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia |

⁸⁰

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

⁸¹

Survey Research Center, Institute for Social Research, Ann Arbor, USA |

⁸²

Translational Gerontology Branch, National institute on Aging, Baltimore, USA |

⁸³

Department of Epidemiology, Gillings School of Global Public health, University of North Carolina, Chapel Hill, USA |

⁸⁴

Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain |

⁸⁵

Moores Cancer Center, University of California San Diego, La Jolla, USA |

⁸⁶

Department of Medical Sciences, University of Trieste, Trieste, Italy |

⁸⁷

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

⁸⁸

Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany |

⁸⁹

German Center for Diabetes Research (DZD), Neuherberg, Germany |

⁹⁰

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia |

⁹¹

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia |

⁹²

Precision Medicine, School of Clinical Sciences At Monash Health, Monash University, Clayton, Australia

Monash University

Monash Health

⁹³

Icelandic Heart Association, Kopavogur, Iceland |

⁹⁴

Faculty of medicine, University of Iceland, Reykjavik, Iceland |

⁹⁵

Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France

Université Paris-Saclay

French Institute of Health and Medical Research

⁹⁶

Department of preventive medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA |

⁹⁷

Institute of Environmental Medicine, Karolinska institutet, Stockholm, Sweden |

⁹⁸

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

⁹⁹

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

¹⁰⁰

Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, USA |

¹⁰¹

BROAD Institute of Harvard and MIT, Cambridge, USA |

¹⁰²

Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands |

¹⁰³

Department of Internal Medicine, The Ohio State University, Columbus, USA |

¹⁰⁴

Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, USA |

¹⁰⁵

Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, USA |

¹⁰⁶

Hebrew SeniorLife Institute for Aging Research, Boston, USA |

¹⁰⁷

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, USA |

¹⁰⁸

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

¹⁰⁹

Faculty of Medicine, University of Split, Split, Croatia |

¹¹⁰

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

¹¹¹

Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, USA |

¹¹²

Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK |

¹¹³

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

¹¹⁴

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the Netherlands |

¹¹⁵

Epidemiology Program, University of Hawaii Cancer Center, Honolulu, USA |

¹¹⁶

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden |

¹¹⁷

Department of Clinical genetics, Karolinska University Hospital, Stockholm, Sweden |

¹¹⁸

Department of Epidemiology, University of Washington, Seattle, USA |

¹¹⁹

Department of Health Sciences Research, Mayo Clinic, Rochester, USA |

¹²⁰

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

¹²¹

Department of Epidemiology, Brown University, Providence, USA |

¹²²

Department of Medicine, Brown University, Providence, USA |

¹²³

NIHR Biomedical Research Centre at Guy’s and St. Thomas’ Foundation Trust, London, UK |

¹²⁴

Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland |

¹²⁵

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

¹²⁶

Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland |

¹²⁷

QIMR Berghofer Medical Research Insititute, Brisbane, Australia |

¹²⁸

Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany |

¹²⁹

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

¹³⁰

Institute for Molecular Bioscience, the University of Queensland, Brisbane, Australia |

¹³¹

Department of Public health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands |

¹³²

Department of Laboratory Medicine and Pathobiology, University Of Toronto, Toronto, Canada |

¹³³

Laboratory Medicine Program, University Health Network, Toronto, Canada |

¹³⁴

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

¹³⁵

Laboratory of Neurogenetics, National Institute On Aging, National Institutes of Health, Bethesda, USA |

¹³⁶

Department of Epidemiology, University of Pittsburgh, Pittsburgh, USA |

¹³⁷

Department of Medicine, University of Pittsburgh, Pittsburgh, USA |

¹³⁸

Department of Internal Medicine, section of gerontology and geriatrics, Leiden University Medical Center, Leiden, The Netherlands |

¹³⁹

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

¹⁴⁰

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

¹⁴¹

Department of Population Science, American Cancer Society, Atlanta, USA |

¹⁴²

Gen-Info Ltd, Zagreb, Croatia |

¹⁴³

Quantify Research, Stockholm, Sweden |

¹⁴⁴

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

Technion – Israel Institute of Technology

Carmel Medical Center

¹⁴⁵

Women’s Health Initiative Branch, National Heart, Lung, and Blood Institute, Bethesda, USA |

¹⁴⁶

Department of Oncology, University Hospital of Larissa, Larissa, Greece |

¹⁴⁷

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

¹⁴⁸

School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy’s Campus, King’s College London, London, UK |

¹⁴⁹

Department of biostatistics, Boston University School of Public Health, Boston, USA |

¹⁵⁰

National Institute on Aging, Intramural Research Program, Baltimore, USA |

¹⁵¹

Division of Molecular Pathology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands |

¹⁵²

Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands |

¹⁵³

Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK |

¹⁵⁴

Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK |

¹⁵⁵

Division of Population and Health Genomics, University of Dundee, Dundee, UK |

¹⁵⁶

Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia |

¹⁵⁷

Population Oncology, BC Cancer, Vancouver, Canada |

¹⁵⁸

School of Population and Public Health, University of British Columbia, Vancouver, CANADA |

¹⁵⁹

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

¹⁶⁰

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

¹⁶¹

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

¹⁶²

Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany |

¹⁶³

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

¹⁶⁴

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany |

¹⁶⁵

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

¹⁶⁶

Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, USA |

¹⁶⁷

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

¹⁶⁸

Department of medicine, internal medicine, Lausanne university hospital and University of Lausanne, Lausanne, Switzerland |

¹⁶⁹

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

¹⁷⁰

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

¹⁷¹

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

¹⁷²

Department of Human genetics, Leiden University Medical Center, Leiden, The Netherlands |

¹⁷³

Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands |

¹⁷⁴

Department of Surgical sciences, Uppsala University, Uppsala, Sweden |

¹⁷⁵

Department of Obstetrics and Gynecology, University Medicine Greifswald, Greifswald, Germany |

¹⁷⁶

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

¹⁷⁷

Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, P.R. China |

¹⁷⁸

Oncode Institute, Utrecht, The Netherlands |

¹⁷⁹

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

¹⁸⁰

MRC Biostatistics Unit, University of Cambridge, Cambridge, UK |

¹⁸¹

Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands |

¹⁸²

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 |

¹⁸³

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany |

¹⁸⁴

Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

University Medical Center Hamburg-Eppendorf

University Cancer Center Hamburg

¹⁸⁵

NHLBI’s and Boston University’s Framingham Heart Study, Framingham, USA

Boston University

National Heart, Lung, and Blood Institute

¹⁸⁶

Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, USA |

¹⁸⁷

Department of paediatrics, University of Cambridge, Cambridge, UK |

Publication type: Journal Article

Publication date: 2021-08-04

Springer Nature

Nature

scimago Q1

wos Q1

SJR: 18.288

CiteScore: 78.1

Impact factor: 48.5

ISSN: 00280836, 14764687

DOI: 10.1038/s41586-021-03779-7

Copy DOI

PubMed ID: 34349265

Multidisciplinary

Abstract

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. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Found

1 citation

Heddar Abdelkader

21 publications, 502 citations

h-index: 9

French Institute of Health and Medical Research

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GOST Copy

Ruth K. S. et al. Genetic insights into biological mechanisms governing human ovarian ageing // Nature. 2021. Vol. 596. No. 7872. pp. 393-397.

GOST all authors (up to 50) Copy

Ruth K. S. et al. Genetic insights into biological mechanisms governing human ovarian ageing // Nature. 2021. Vol. 596. No. 7872. pp. 393-397.

RIS |

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RIS

BibTex |

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BibTex (up to 50 authors) Copy

@article{2021_Ruth,

author = {Katherine S. Ruth and Felix R. Day and Jazib Hussain and Ana Martínez Marchal and Catherine E. Aiken and Ajuna Azad and Deborah J. Thompson and Lucie Knoblochova and Hironori Abe and Jane L. Tarry-Adkins and Javier Martin Gonzalez and Pierre Fontanillas and Annique Claringbould and Olivier B Bakker and Patrick Sulem and Robin G. Walters and Chikashi Terao and Sandra Turon and Momoko Horikoshi and Kuang Lin and N. Charlotte Onland-Moret and Aditya Sankar and Emil Peter Thrane Hertz and Pascal N Timshel and Vallari Shukla and Rehannah Borup and Kristina W Olsen and Paula Aguilera and Mònica Ferrer Roda and Yan Huang and Stasa Stankovic and Paul R H J Timmers and Thomas U. Ahearn and Behrooz Z. Alizadeh and Elnaz Naderi and Irene L. Andrulis and Alice M Arnold and Kristan J Aronson and Annelie Augustinsson and Stefania Bandinelli and Caterina M Barbieri and Robin N Beaumont and Heiko Becher and Matthias W. Beckmann and Stefania Benónísdóttir and Sven Bergmann and Murielle Bochud and Eric Boerwinkle and Stig E. Bojesen and Manjeet K. Bolla and others},

title = {Genetic insights into biological mechanisms governing human ovarian ageing},

journal = {Nature},

year = {2021},

volume = {596},

publisher = {Springer Nature},

month = {aug},

url = {https://doi.org/10.1038/s41586-021-03779-7},

number = {7872},

pages = {393--397},

doi = {10.1038/s41586-021-03779-7}

}

MLA

Cite this

MLA Copy

Ruth, Katherine S., et al. “Genetic insights into biological mechanisms governing human ovarian ageing.” Nature, vol. 596, no. 7872, Aug. 2021, pp. 393-397. https://doi.org/10.1038/s41586-021-03779-7.

Publisher

Springer Nature

Journal

Nature

scimago Q1

wos Q1

SJR

18.288

CiteScore

78.1

Impact factor

48.5

ISSN

00280836 (Print)

14764687 (Electronic)