Genetic insights into biological mechanisms governing human ovarian ageing,Nature

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Genetic insights into biological mechanisms governing human ovarian ageing
Nature ( IF 64.8 ) Pub Date : 2021-08-04 , DOI: 10.1038/s41586-021-03779-7
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 Benonisdottir 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 , Tõnu 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} , Pascal Guénel 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} , Zoltan Kutalik _{44,

45} , Martina La Bianca ₅₉ , Genevieve LaChance ₁₁₂ , Claudia Langenberg ₂ , Lenore J Launer ₁₁₃ , Joop S E Laven ₁₁₄ , Deborah A Lawlor _{69,

70} , Loic Le Marchand ₁₁₅ , Jingmei Li ₆₈ , Annika Lindblom _{116,

117} , Sara Lindstrom 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} , Arto Mannermaa _{124,

125,

126} , Brumat Marco 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 , Håkan 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 Polasek _{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 Þorsteinsdottir _{16,

165} , Nicholas J Timpson _{69,

70} , Daniela Toniolo ₄₀ , Michela Traglia ₄₀ , Melissa A Troester ₁₄₀ , Thérèse Truong ₉₅ , Jessica Tyrrell ₁ , André 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} , Eva R Hoffmann ₃ , Anna Murray ₁ , Ignasi Roig _{4,

5} , John R B Perry _{2,

54}

Affiliation

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.
DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Libechov, Czech Republic.
Faculty of Science, Charles University, Prague, Czech Republic.
Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Transgenic Core Facility, Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
23andMe Inc., Sunnyvale, CA, USA.
Structural and Computational Biology Unit, EMBL, Heidelberg, Germany.
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
deCODE genetics/Amgen, Reykjavik, Iceland.
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
MRC Population Health Research Unit, University of Oxford, Oxford, UK.
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Transgenic Animal Unit, Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
Laboratory for Genomics of Diabetes and Metabolism, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Reproductive Medicine, Department of Obstetrics and Gynaecology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Sevilla -Universidad Pablo de Olavide, Seville, Spain.
Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada.
Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
University Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland.
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Amsterdam Public Health (APH) Research Institute, Amsterdam, The Netherlands.
Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam, The Netherlands.
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Brigham and Women's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', Trieste, Italy.
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Institute of Genetics and Biophysics - CNR, Naples, Italy.
IRCCS Neuromed, Pozzilli, Isernia, Italy.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy.
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
University of Sassari, Department of Biomedical Sciences, Sassari, Italy.
Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Division of Epidemiology & Community Health, University of Minnesotta, Minneapolis, MN, USA.
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
School of Life Sciences, University of Westminster, London, UK.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Population and Medical Genetics, Broad Institute, Cambridge, MA, USA.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
Survey Research Center, Institute for Social Research, Ann Arbor, MI, USA.
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
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.
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Department of Medical Sciences, University of Trieste, Trieste, Italy.
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
Icelandic Heart Association, Kopavogur, Iceland.
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Division of Medical Oncology, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
The Cancer Prevention and Control Research Program, University of Kentucky Markey Cancer Center, Lexington, KY, USA.
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Hebrew SeniorLife Institute for Aging Research, Boston, MA, USA.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Faculty of Medicine, University of Split, Split, Croatia.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Department of Epidemiology, University of Washington, Seattle, WA, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Wake Forest, NC, USA.
Department of Epidemiology, Brown University, Providence, RI, USA.
Department of Medicine, Brown University, Providence, RI, USA.
NIHR Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK.
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
QIMR Berghofer Medical Research Insititute, Brisbane, Queensland, Australia.
Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany.
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
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 Population Science, American Cancer Society, Atlanta, GA, USA.
Gen-Info Ltd, Zagreb, Croatia.
Quantify Research, Stockholm, Sweden.
Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
Women's Health Initiative Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Department of Oncology, University Hospital of Larissa, Larissa, Greece.
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
National Institute on Aging, Intramural Research Program, Baltimore, MD, USA.
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.
Division of Population and Health Genomics, University of Dundee, Dundee, UK.
Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
Population Oncology, BC Cancer, Vancouver, British Columbia, Canada.
School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Department of Obstetrics and Gynecology, University Medicine Greifswald, Greifswald, Germany.
School of Public Health, Peking University Health Science Center, Beijing, P.R. China.
Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, P.R. China.
Oncode Institute, Utrecht, The Netherlands.
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
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.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
NHLBI's and Boston University's Framingham Heart Study, Framingham, MA, USA.
Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, MA, USA.
Department of Paediatrics, University of Cambridge, Cambridge, UK.

Reproductive longevity is essential for fertility and influences healthy ageing in women^1,2, 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.

中文翻译：

对控制人类卵巢衰老的生物学机制的遗传洞察

生殖寿命对于生育能力至关重要，并影响女性的健康老龄化^1,2，但对其潜在的生物学机制和保护它的治疗方法的了解是有限的。在这里，我们确定了 290 种卵巢衰老的遗传决定因素，这些因素使用约 200,000 名欧洲血统女性的自然绝经 (ANM) 年龄的正常变化进行了评估。这些常见等位基因与 ANM 的临床极端情况相关；遗传易感性排名前 1% 的女性患卵巢功能不全的风险与携带单基因FMR1前突变的女性相同³. 已识别的位点涉及广泛的 DNA 损伤反应 (DDR) 过程，包括关键 DDR 相关基因中的功能丧失变异。与实验模型的整合表明，这些 DDR 过程在整个生命过程中起作用，以塑造卵巢储备及其耗竭率。此外，我们证明了对人类遗传学强调的 DDR 通路的实验操作可提高小鼠的生育能力并延长其生殖寿命。使用已识别的遗传变异进行因果推断分析表明，延长女性的生殖寿命可以改善骨骼健康并降低患 2 型糖尿病的风险，但会增加患激素敏感性癌症的风险。这些发现提供了对控制卵巢衰老的机制的深入了解，当它们起作用时，

更新日期：2021-08-04

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