Genetic insights into biological mechanisms governing human ovarian ageing

Katherine S. Ruth, Felix R. Day, Jazib Hussain, Ana Martínez-Marchal, Catherine E. Aiken, Ajuna Azad, Deborah J. Thompson, Lucie Knoblochova, Hironori Abe, Jane L. Tarry-Adkins, Javier Martin Gonzalez, Pierre Fontanillas, Annique Claringbould, Olivier B. Bakker, Patrick Sulem, Robin G. Walters, Chikashi Terao, Sandra Turon, Momoko Horikoshi, Kuang Lin, N. Charlotte Onland-Moret, Aditya Sankar, Emil Peter Thrane Hertz, Pascal N. Timshel, Vallari Shukla, Rehannah Borup, Kristina W. Olsen, Paula Aguilera, Mònica Ferrer-Roda, Yan Huang, Stasa Stankovic, Paul R. H. J. Timmers, Thomas U. Ahearn, Behrooz Z. Alizadeh, Elnaz Naderi, Irene L. Andrulis, Alice M. Arnold, Kristan J. Aronson, Annelie Augustinsson, Stefania Bandinelli, Caterina M. Barbieri, Robin N. Beaumont, Heiko Becher, Matthias W. Beckmann, Stefania Benonisdottir, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E. Bojesen, Manjeet K. Bolla, Dorret I. Boomsma, Nicholas Bowker, Jennifer A. Brody, Linda Broer, Julie E. Buring, Archie Campbell, Harry Campbell, Jose E. Castelao, Eulalia Catamo, Stephen J. Chanock, Georgia Chenevix-Trench, Marina Ciullo, Tanguy Corre, Fergus J. Couch, Angela Cox, Laura Crisponi, Simon S. Cross, Francesco Cucca, Kamila Czene, George Davey Smith, Eco J. C. N. Geus, Renée Mutsert, Immaculata Vivo, Ellen W. Demerath, Joe Dennis, Alison M. Dunning, Miriam Dwek, Mikael Eriksson, Tõnu Esko, Peter A. Fasching, Jessica D. Faul, Luigi Ferrucci, Nora Franceschini, Timothy M. Frayling, Manuela Gago-Dominguez, Massimo Mezzavilla, Montserrat García-Closas, Christian Gieger, Graham G. Giles, Harald Grallert, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Caroline Hayward, Chunyan He, Wei He, Gerardo Heiss, Miya K. Høffding, John L. Hopper, Jouke J. Hottenga, Frank Hu, David Hunter, Mohammad A. Ikram, Rebecca D. Jackson, Micaella D. R. Joaquim, Esther M. John, Peter K. Joshi, David Karasik, Sharon L. R. Kardia, Christiana Kartsonaki, Robert Karlsson, Cari M. Kitahara, Ivana Kolcic, Charles Kooperberg, Peter Kraft, Allison W. Kurian, Zoltan Kutalik, Martina Bianca, Genevieve LaChance, Claudia Langenberg, Lenore J. Launer, Joop S. E. Laven, Deborah A. Lawlor, Loic Marchand, Jingmei Li, Annika Lindblom, Sara Lindstrom, Tricia Lindstrom, Martha Linet, YongMei Liu, Simin Liu, Jian’an Luan, Reedik Mägi, Patrik K. E. Magnusson, Massimo Mangino, Arto Mannermaa, Brumat Marco, Jonathan Marten, Nicholas G. Martin, Hamdi Mbarek, Barbara McKnight, Sarah E. Medland, Christa Meisinger, Thomas Meitinger, Cristina Menni, Andres Metspalu, Lili Milani, Roger L. Milne, Grant W. Montgomery, Dennis O. Mook-Kanamori, Antonella Mulas, Anna M. Mulligan, Alison Murray, Mike A. Nalls, Anne Newman, Raymond Noordam, Teresa Nutile, Dale R. Nyholt, Andrew F. Olshan, Håkan Olsson, Jodie N. Painter, Alpa V. Patel, Nancy L. Pedersen, Natalia Perjakova, Annette Peters, Ulrike Peters, Paul D. P. Pharoah, Ozren Polasek, Eleonora Porcu, Bruce M. Psaty, Iffat Rahman, Gad Rennert, Hedy S. Rennert, Paul M. Ridker, Susan M. Ring, Antonietta Robino, Lynda M. Rose, Frits R. Rosendaal, Jacques Rossouw, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Cinzia F. Sala, Emmanouil Saloustros, Dale P. Sandler, Serena Sanna, Elinor J. Sawyer, Chloé Sarnowski, David Schlessinger, Marjanka K. Schmidt, Minouk J. Schoemaker, Katharina E. Schraut, Christopher Scott, Saleh Shekari, Amruta Shrikhande, Albert V. Smith, Blair H. Smith, Jennifer A. Smith, Rossella Sorice, Melissa C. Southey, Tim D. Spector, John J. Spinelli, Meir Stampfer, Doris Stöckl, Joyce B. J. Meurs, Konstantin Strauch, Unnur Styrkarsdottir, Anthony J. Swerdlow, Toshiko Tanaka, Lauren R. Teras, Alexander Teumer, Unnur Þorsteinsdottir, Nicholas J. Timpson, Daniela Toniolo, Michela Traglia, Melissa A. Troester, Thérèse Truong, Jessica Tyrrell, André G. Uitterlinden, Sheila Ulivi, Celine M. Vachon, Veronique Vitart, Uwe Völker, Peter Vollenweider, Henry Völzke, Qin Wang, Nicholas J. Wareham, Clarice R. Weinberg, David R. Weir, Amber N. Wilcox, Ko Willems Dijk, Gonneke Willemsen, James F. Wilson, Bruce H. R. Wolffenbuttel, Alicja Wolk, Andrew R. Wood, Wei Zhao, Marek Zygmunt, Zhengming Chen, Liming Li, Lude Franke, Stephen Burgess, Patrick Deelen, Tune H. Pers, Marie Louise Grøndahl, Claus Yding Andersen, Anna Pujol, Andres J. Lopez-Contreras, Jeremy A. Daniel, Kari Stefansson, Jenny Chang-Claude, Yvonne T. van der Schouw, Kathryn L. Lunetta, Daniel I. Chasman, Douglas F. Easton, Jenny A. Visser, Susan E. Ozanne, Satoshi H. Namekawa, Petr Solc, Joanne M. Murabito, Ken K. Ong, Eva R. Hoffmann (), Anna Murray (), Ignasi Roig () and John R. B. Perry ()
Additional contact information
Katherine S. Ruth: University of Exeter Medical School, University of Exeter
Felix R. Day: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Jazib Hussain: University of Copenhagen
Ana Martínez-Marchal: Universitat Autònoma de Barcelona
Catherine E. Aiken: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome–MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Ajuna Azad: University of Copenhagen
Deborah J. Thompson: University of Cambridge
Lucie Knoblochova: Institute of Animal Physiology and Genetics of the Czech Academy of Sciences
Hironori Abe: Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center
Jane L. Tarry-Adkins: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome–MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Javier Martin Gonzalez: University of Copenhagen
Pierre Fontanillas: 23andMe Inc.
Annique Claringbould: Structural and Computational Biology Unit, EMBL
Olivier B. Bakker: University of Groningen, University Medical Center Groningen, Department of Genetics
Patrick Sulem: deCODE genetics/Amgen
Robin G. Walters: University of Oxford
Chikashi Terao: Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences
Sandra Turon: Universitat Autònoma de Barcelona
Momoko Horikoshi: Laboratory for Genomics of Diabetes and Metabolism, RIKEN Center for Integrative Medical Sciences
Kuang Lin: University of Oxford
N. Charlotte Onland-Moret: University Medical Center Utrecht, Utrecht University
Aditya Sankar: University of Copenhagen
Emil Peter Thrane Hertz: University of Copenhagen
Pascal N. Timshel: University of Copenhagen
Vallari Shukla: University of Copenhagen
Rehannah Borup: University of Copenhagen
Kristina W. Olsen: University of Copenhagen
Paula Aguilera: University of Copenhagen
Mònica Ferrer-Roda: Universitat Autònoma de Barcelona
Yan Huang: Universitat Autònoma de Barcelona
Stasa Stankovic: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Paul R. H. J. Timmers: University of Edinburgh
Thomas U. Ahearn: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
Behrooz Z. Alizadeh: University Medical Center Groningen, University of Groningen
Elnaz Naderi: University Medical Center Groningen, University of Groningen
Irene L. Andrulis: Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Alice M. Arnold: University of Washington
Kristan J. Aronson: Queen’s University
Annelie Augustinsson: Lund University
Stefania Bandinelli: Geriatric Unit, Azienda Sanitaria Firenze (ASF)
Caterina M. Barbieri: Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute
Robin N. Beaumont: University of Exeter Medical School, University of Exeter
Heiko Becher: University Medical Center Hamburg-Eppendorf
Matthias W. Beckmann: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Stefania Benonisdottir: deCODE genetics/Amgen
Sven Bergmann: University of Lausanne
Murielle Bochud: University Center for Primary Care and Public Health, University of Lausanne
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Stig E. Bojesen: Copenhagen University Hospital
Manjeet K. Bolla: University of Cambridge
Dorret I. Boomsma: Vrije Universiteit Amsterdam
Nicholas Bowker: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Jennifer A. Brody: University of Washington
Linda Broer: Erasmus MC
Julie E. Buring: Brigham and Women’s Hospital
Archie Campbell: University of Edinburgh
Harry Campbell: University of Edinburgh
Jose E. Castelao: Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS
Eulalia Catamo: Institute for Maternal and Child Health – IRCCS ‘Burlo Garofolo’
Stephen J. Chanock: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
Georgia Chenevix-Trench: QIMR Berghofer Medical Research Institute
Marina Ciullo: Institute of Genetics and Biophysics – CNR
Tanguy Corre: University of Lausanne
Fergus J. Couch: Mayo Clinic
Angela Cox: University of Sheffield
Laura Crisponi: Institute of Genetics and Biomedical Research, National Research Council
Simon S. Cross: University of Sheffield
Francesco Cucca: Institute of Genetics and Biomedical Research, National Research Council
Kamila Czene: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics
George Davey Smith: University of Bristol
Eco J. C. N. Geus: Vrije Universiteit Amsterdam
Renée Mutsert: Leiden University Medical Center
Immaculata Vivo: Harvard T. H. Chan School of Public Health
Ellen W. Demerath: University of Minnesotta
Joe Dennis: University of Cambridge
Alison M. Dunning: University of Cambridge
Miriam Dwek: University of Westminster
Mikael Eriksson: Karolinska Institutet
Tõnu Esko: Population and Medical Genetics, Broad Institute
Peter A. Fasching: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Jessica D. Faul: Survey Research Center, Institute for Social Research
Luigi Ferrucci: Translational Gerontology Branch, National Institute on Aging
Nora Franceschini: University of North Carolina
Timothy M. Frayling: University of Exeter Medical School, University of Exeter
Manuela Gago-Dominguez: Complejo Hospitalario Universitario de Santiago, SERGAS
Massimo Mezzavilla: University of Trieste
Montserrat García-Closas: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
Christian Gieger: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health
Graham G. Giles: Cancer Epidemiology Division, Cancer Council Victoria
Harald Grallert: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health
Daniel F. Gudbjartsson: deCODE genetics/Amgen
Vilmundur Gudnason: Icelandic Heart Association
Pascal Guénel: University Paris-Sud, University Paris-Saclay
Christopher A. Haiman: University of Southern California
Niclas Håkansson: Institute of Environmental Medicine, Karolinska Institutet
Per Hall: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics
Caroline Hayward: University of Edinburgh, Western General Hospital
Chunyan He: University of Kentucky College of Medicine
Wei He: Karolinska Institutet
Gerardo Heiss: University of North Carolina
Miya K. Høffding: University of Copenhagen
John L. Hopper: The University of Melbourne
Jouke J. Hottenga: Vrije Universiteit Amsterdam
Frank Hu: Harvard T. H. Chan School of Public Health
David Hunter: University of Oxford
Mohammad A. Ikram: Erasmus MC
Rebecca D. Jackson: The Ohio State University
Micaella D. R. Joaquim: University of Exeter Medical School, University of Exeter
Esther M. John: Stanford University School of Medicine
Peter K. Joshi: University of Edinburgh
David Karasik: Harvard Medical School
Sharon L. R. Kardia: University of Michigan
Christiana Kartsonaki: University of Oxford
Robert Karlsson: Karolinska Institutet
Cari M. Kitahara: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Ivana Kolcic: University of Split
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Peter Kraft: Harvard T. H. Chan School of Public Health
Allison W. Kurian: Stanford University School of Medicine
Zoltan Kutalik: Swiss Institute of Bioinformatics
Martina Bianca: Institute for Maternal and Child Health – IRCCS ‘Burlo Garofolo’
Genevieve LaChance: King’s College London
Claudia Langenberg: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Lenore J. Launer: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health
Joop S. E. Laven: Erasmus University Medical Center
Deborah A. Lawlor: University of Bristol
Loic Marchand: University of Hawaii Cancer Center
Jingmei Li: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics
Annika Lindblom: Karolinska Institutet
Sara Lindstrom: University of Washington
Tricia Lindstrom: Mayo Clinic
Martha Linet: Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute
YongMei Liu: Wake Forest School of Medicine
Simin Liu: Brown University
Jian’an Luan: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Reedik Mägi: University of Tartu
Patrik K. E. Magnusson: Karolinska Institutet
Massimo Mangino: King’s College London
Arto Mannermaa: University of Eastern Finland
Brumat Marco: University of Trieste
Jonathan Marten: University of Edinburgh, Western General Hospital
Nicholas G. Martin: QIMR Berghofer Medical Research Insititute
Hamdi Mbarek: Vrije Universiteit Amsterdam
Barbara McKnight: University of Washington
Sarah E. Medland: QIMR Berghofer Medical Research Insititute
Christa Meisinger: Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health
Thomas Meitinger: German Research Center for Environmental Health
Cristina Menni: King’s College London
Andres Metspalu: University of Tartu
Lili Milani: University of Tartu
Roger L. Milne: Cancer Epidemiology Division, Cancer Council Victoria
Grant W. Montgomery: The University of Queensland
Dennis O. Mook-Kanamori: Leiden University Medical Center
Antonella Mulas: Institute of Genetics and Biomedical Research, National Research Council
Anna M. Mulligan: University of Toronto
Alison Murray: University of Aberdeen
Mike A. Nalls: National Institutes of Health
Anne Newman: University of Pittsburgh
Raymond Noordam: Leiden University Medical Center
Teresa Nutile: Institute of Genetics and Biophysics – CNR
Dale R. Nyholt: Queensland University of Technology
Andrew F. Olshan: University of North Carolina at Chapel Hill
Håkan Olsson: Lund University
Jodie N. Painter: QIMR Berghofer Medical Research Insititute
Alpa V. Patel: American Cancer Society
Nancy L. Pedersen: Karolinska Institutet
Natalia Perjakova: University of Tartu
Annette Peters: Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health
Ulrike Peters: Fred Hutchinson Cancer Research Center
Paul D. P. Pharoah: University of Cambridge
Ozren Polasek: University of Split
Eleonora Porcu: Institute of Genetics and Biomedical Research, National Research Council
Bruce M. Psaty: University of Washington
Iffat Rahman: Quantify Research
Gad Rennert: Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine
Hedy S. Rennert: Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine
Paul M. Ridker: Brigham and Women’s Hospital
Susan M. Ring: University of Bristol
Antonietta Robino: Institute for Maternal and Child Health – IRCCS ‘Burlo Garofolo’
Lynda M. Rose: Brigham and Women’s Hospital
Frits R. Rosendaal: Leiden University Medical Center
Jacques Rossouw: Women’s Health Initiative Branch, National Heart, Lung, and Blood Institute
Igor Rudan: University of Edinburgh
Rico Rueedi: University of Lausanne
Daniela Ruggiero: Institute of Genetics and Biophysics – CNR
Cinzia F. Sala: Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute
Emmanouil Saloustros: University Hospital of Larissa
Dale P. Sandler: Epidemiology Branch, National Institute of Environmental Health Sciences, NIH
Serena Sanna: Institute of Genetics and Biomedical Research, National Research Council
Elinor J. Sawyer: Guy’s Campus, King’s College London
Chloé Sarnowski: Boston University School of Public Health
David Schlessinger: Intramural Research Program
Marjanka K. Schmidt: The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital
Minouk J. Schoemaker: The Institute of Cancer Research
Katharina E. Schraut: University of Edinburgh
Christopher Scott: Mayo Clinic
Saleh Shekari: University of Exeter Medical School, University of Exeter
Amruta Shrikhande: University of Copenhagen
Albert V. Smith: Icelandic Heart Association
Blair H. Smith: University of Dundee
Jennifer A. Smith: University of Michigan
Rossella Sorice: Institute of Genetics and Biophysics – CNR
Melissa C. Southey: Cancer Epidemiology Division, Cancer Council Victoria
Tim D. Spector: King’s College London
John J. Spinelli: Population Oncology, BC Cancer
Meir Stampfer: Harvard T. H. Chan School of Public Health
Doris Stöckl: Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health
Joyce B. J. Meurs: Erasmus MC
Konstantin Strauch: Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health
Unnur Styrkarsdottir: deCODE genetics/Amgen
Anthony J. Swerdlow: The Institute of Cancer Research
Toshiko Tanaka: Translational Gerontology Branch, National Institute on Aging
Lauren R. Teras: American Cancer Society
Alexander Teumer: University Medicine Greifswald
Unnur Þorsteinsdottir: deCODE genetics/Amgen
Nicholas J. Timpson: University of Bristol
Daniela Toniolo: Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute
Michela Traglia: Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute
Melissa A. Troester: University of North Carolina at Chapel Hill
Thérèse Truong: University Paris-Sud, University Paris-Saclay
Jessica Tyrrell: University of Exeter Medical School, University of Exeter
André G. Uitterlinden: Erasmus MC
Sheila Ulivi: Institute for Maternal and Child Health – IRCCS ‘Burlo Garofolo’
Celine M. Vachon: Mayo Clinic
Veronique Vitart: University of Edinburgh, Western General Hospital
Uwe Völker: University Medicine Greifswald
Peter Vollenweider: Lausanne University Hospital and University of Lausanne
Henry Völzke: University Medicine Greifswald
Qin Wang: University of Cambridge
Nicholas J. Wareham: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Clarice R. Weinberg: Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH
David R. Weir: Survey Research Center, Institute for Social Research
Amber N. Wilcox: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
Ko Willems Dijk: Leiden University Medical Center
Gonneke Willemsen: Vrije Universiteit Amsterdam
James F. Wilson: University of Edinburgh
Bruce H. R. Wolffenbuttel: University Medical Center Groningen, University of Groningen
Alicja Wolk: Institute of Environmental Medicine, Karolinska Institutet
Andrew R. Wood: University of Exeter Medical School, University of Exeter
Wei Zhao: University of Michigan
Marek Zygmunt: University Medicine Greifswald
Zhengming Chen: University of Oxford
Liming Li: Peking University Health Science Center
Lude Franke: University of Groningen, University Medical Center Groningen, Department of Genetics
Stephen Burgess: University of Cambridge
Patrick Deelen: University of Groningen, University Medical Center Groningen, Department of Genetics
Tune H. Pers: University of Copenhagen
Marie Louise Grøndahl: Copenhagen University Hospital
Claus Yding Andersen: Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen
Anna Pujol: Universitat Autònoma de Barcelona
Andres J. Lopez-Contreras: University of Copenhagen
Jeremy A. Daniel: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Kari Stefansson: deCODE genetics/Amgen
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Yvonne T. van der Schouw: University Medical Center Utrecht, Utrecht University
Kathryn L. Lunetta: Boston University School of Public Health
Daniel I. Chasman: Brigham and Women’s Hospital
Douglas F. Easton: University of Cambridge
Jenny A. Visser: Erasmus MC
Susan E. Ozanne: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome–MRC Institute of Metabolic Science, Addenbrooke’s Hospital
Satoshi H. Namekawa: Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center
Petr Solc: Institute of Animal Physiology and Genetics of the Czech Academy of Sciences
Joanne M. Murabito: NHLBI’s and Boston University’s Framingham Heart Study
Ken K. Ong: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus
Eva R. Hoffmann: University of Copenhagen
Anna Murray: University of Exeter Medical School, University of Exeter
Ignasi Roig: Universitat Autònoma de Barcelona
John R. B. Perry: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus

Nature, 2021, vol. 596, issue 7872, 393-397

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03779-7

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