閉経時期を左右する卵巣の老化の主要な決定因子

//背景//---
まずは「何をするにも体が資本」という考え方があります。
身体が健康でなければ、様々な活動が制限されるからです。
心技体という言葉もありますが、
同じように心の健康に対しても当てはまります。
これから日本だけではなく世界でも高齢化が進むことから、
人生の後半において、ただ生き延びるだけではなく
その中でどうやったら健康状態を維持できるか？
これについて世界的に考えていくことになります。
女性の場合には少なくとも一部の人においては
出産というイベントがあり、
ほぼすべての人が閉経も経験します。
その際に大きくホルモンバランスが変わる事から、
それによる健康への影響を考える必要性が出てきます。
閉経は40歳から55歳くらいと個人差があります。
おおよそ50歳から52歳くらいの人が多いとされています(2)。
このような閉経のタイミング(Reproductive longevity)と
女性の健康について議論されています(3,4)。
一般的には生殖可能な状態を長く続ける事は
骨の健康や2型糖尿病のリスクを減らすことが示されています(5,6)。
一方でホルモンに関係する乳がんなどのリスクを高めるといわれています。
また生活習慣としては、
アルコールの摂取、喫煙は閉経のタイミングを早めるとされています(1)。
従って、閉経のタイミングの早い、遅いについて
現時点で一義的にその是非を論じる事はできませんが、
女性の健康を考える上で一つの重要なイベントであるということです。
---
Katherine S. Ruth, Felix R. Day, Jazib Hussain, Ana Martínez-Marchalら
国際的な医療研究グループは、
女性の卵巣の老化の生物学的な機序に関わる遺伝子について報告しています(1)。
本日はその内容の一部を自身の視点を加えながら
読者の方と情報共有したいと思います。

//閉経の生物学//---
女性は閉経を迎える10年前くらいから
卵子の元となる卵母細胞の遺伝子的な完全性(遺伝子不安定性)が低下する
と考えられています(7)。
おおよそ平均的に50歳くらいで閉経するとすると
10年前というと40歳ですから、
高齢出産の一つのリスクはこの卵巣の卵母細胞の
遺伝子の状態の変化と関係している可能性が考えられます。
このような卵母細胞の遺伝子的な不完全性などを含む
生殖能力に関する老化を主に制御しているのは
卵巣のDNAのダメージ反応(DNA damage response(DDR)であると
ゲノム解析、動物モデル、卵巣疾患モデルから指摘されています(8-10)。

//変異遺伝子(一部抜粋)//---
ヨーロッパ系の先祖20万人の
290種類の卵巣の老化に関わるの遺伝子の決定因子を明らかにしています(1)。
ー
*Independent predicted-deleterious variants
MCM8, EXO1, HELB, C1orf112, C19orf57, FANCM and FANCA
*LOF variants 
BRCA1, BRCA2 and CHEK2 

//論点//---
生殖能力に関連する卵巣の老化を制御している主な要因の一つは
DNAのダメージ反応によるので、
このダメージ反応を緩和する事が卵巣の寿命を延ばす、
老化を防ぐために必要になります。
一方、
このような卵巣の老化は閉経後において
女性の健康状態にどのような影響を与えるか
というのも重要な視点です。
すでに閉経している人に対して
卵巣のDNAダメージ反応の抑制のための医療、生活習慣改善に
価値があるかどうか決定する要因だからです。

//治療の可能性について//---
CHEK1はDNA修復の際に重要な役割を果たすことが知られています(11)。
Katherine S氏らの報告によれば
卵細胞を提供する卵巣の能力である卵巣予備能(Ovarian reserve)が
この遺伝子の発現能力を高めることで向上したことが
マウスのモデルで示されています(1)。
従って、この遺伝子に作用するような治療が視点として存在します。

//Discussion//---
 The ovarian aging is highly associated with the DNA damage response. Therefore, protecting ovaria from DNA damage is important for ovarian health and elongation of reproductive capacity. Whether ovarian health by alleviation of DNA damage is valuable also for the menopause women is one of the perspectives in the future aging society. Clarifying association with the lifestyle including /alcohol consumption, exercise, mental health, and diet/, may be valuable. 

(Reference)
(1)
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. de Geus, Renée de Mutsert, Immaculata De 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 La Bianca, Genevieve LaChance, Claudia Langenberg, Lenore J. Launer, Joop S. E. Laven, Deborah A. Lawlor, Loic Le 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. van 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 van Dijk, Gonneke Willemsen, James F. Wilson, Bruce H. R. Wolffenbuttel, Alicja Wolk, Andrew R. Wood, Wei Zhao, Marek Zygmunt, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, The Biobank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, The LifeLines Cohort Study, The InterAct consortium, 23andMe Research Team, 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 & John R. B. Perry 
Genetic insights into biological mechanisms governing human ovarian ageing
---
Author information
Author notes
These authors jointly supervised this work: Eva R. Hoffmann, Anna Murray, Ignasi Roig, John R. B. Perry
Deceased
These authors contributed equally: Katherine S. Ruth, Felix R. Day, Jazib Hussain, Ana Martínez-Marchal
Affiliations
Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK
Katherine S. Ruth, Robin N. Beaumont, Timothy M. Frayling, Micaella D. R. Joaquim, Saleh Shekari, Jessica Tyrrell, Andrew R. Wood & Anna Murray
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
Felix R. Day, Stasa Stankovic, Nicholas Bowker, Claudia Langenberg, Jian’an Luan, Nicholas J. Wareham, Ken K. Ong & John R. B. Perry
DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Jazib Hussain, Ajuna Azad, Aditya Sankar, Emil Peter Thrane Hertz, Vallari Shukla, Rehannah Borup, Kristina W. Olsen, Paula Aguilera, Miya K. Høffding, Amruta Shrikhande, Andres J. Lopez-Contreras & Eva R. Hoffmann
Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
Ana Martínez-Marchal, Mònica Ferrer-Roda, Yan Huang & Ignasi Roig
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
Ana Martínez-Marchal, Mònica Ferrer-Roda, Yan Huang & Ignasi Roig
University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome–MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
Catherine E. Aiken, Jane L. Tarry-Adkins & Susan E. Ozanne
Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
Catherine E. Aiken & Jane L. Tarry-Adkins
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Deborah J. Thompson, Manjeet K. Bolla, Joe Dennis, Paul D. P. Pharoah, Qin Wang & Douglas F. Easton
Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Libechov, Czech Republic
Lucie Knoblochova & Petr Solc
Faculty of Science, Charles University, Prague, Czech Republic
Lucie Knoblochova
Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Hironori Abe & Satoshi H. Namekawa
Transgenic Core Facility, Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Javier Martin Gonzalez
23andMe Inc., Sunnyvale, CA, USA
Pierre Fontanillas
Structural and Computational Biology Unit, EMBL, Heidelberg, Germany
Annique Claringbould
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
Olivier B. Bakker, Lude Franke & Patrick Deelen
deCODE genetics/Amgen, Reykjavik, Iceland
Patrick Sulem, Stefania Benonisdottir, Daniel F. Gudbjartsson, Unnur Styrkarsdottir, Unnur Þorsteinsdottir & Kari Stefansson
Nuffield Department of Population Health, University of Oxford, Oxford, UK
Robin G. Walters, Kuang Lin, David Hunter, Christiana Kartsonaki & Zhengming Chen
MRC Population Health Research Unit, University of Oxford, Oxford, UK
Robin G. Walters, Christiana Kartsonaki & Zhengming Chen
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Chikashi Terao
Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
Chikashi Terao
Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
Chikashi Terao
Transgenic Animal Unit, Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
Sandra Turon & Anna Pujol
Laboratory for Genomics of Diabetes and Metabolism, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Momoko Horikoshi
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
N. Charlotte Onland-Moret & Yvonne T. van der Schouw
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Emil Peter Thrane Hertz & Jeremy A. Daniel
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Pascal N. Timshel & Tune H. Pers
Reproductive Medicine, Department of Obstetrics and Gynaecology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Kristina W. Olsen & Marie Louise Grøndahl
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC) – Universidad de Sevilla –Universidad Pablo de Olavide, Seville, Spain
Paula Aguilera & Andres J. Lopez-Contreras
Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK
Paul R. H. J. Timmers, Harry Campbell, Peter K. Joshi, Igor Rudan, Katharina E. Schraut & James F. Wilson
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK
Paul R. H. J. Timmers, Caroline Hayward, Jonathan Marten, Veronique Vitart & James F. Wilson
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
Thomas U. Ahearn, Stephen J. Chanock, Montserrat García-Closas & Amber N. Wilcox
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Behrooz Z. Alizadeh & Elnaz Naderi
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
Irene L. Andrulis
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
Irene L. Andrulis
Department of Biostatistics, University of Washington, Seattle, WA, USA
Alice M. Arnold & Barbara McKnight
Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada
Kristan J. Aronson
Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada
Kristan J. Aronson
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
Annelie Augustinsson & Håkan Olsson
Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy
Stefania Bandinelli
Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Caterina M. Barbieri, Cinzia F. Sala, Daniela Toniolo & Michela Traglia
Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Heiko Becher
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
Matthias W. Beckmann & Peter A. Fasching
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
Sven Bergmann, Tanguy Corre & Rico Rueedi
Swiss Institute of Bioinformatics, Lausanne, Switzerland
Sven Bergmann, Tanguy Corre, Zoltan Kutalik & Rico Rueedi
University Center for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland
Murielle Bochud, Tanguy Corre & Zoltan Kutalik
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
Eric Boerwinkle
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Stig E. Bojesen
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Stig E. Bojesen
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Stig E. Bojesen
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Dorret I. Boomsma, Eco J. C. N. de Geus, Jouke J. Hottenga, Hamdi Mbarek & Gonneke Willemsen
Amsterdam Public Health (APH) Research Institute, Amsterdam, The Netherlands
Dorret I. Boomsma, Eco J. C. N. de Geus, Jouke J. Hottenga, Hamdi Mbarek & Gonneke Willemsen
Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam, The Netherlands
Dorret I. Boomsma, Eco J. C. N. de Geus, Jouke J. Hottenga, Hamdi Mbarek & Gonneke Willemsen
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA
Jennifer A. Brody & Bruce M. Psaty
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Linda Broer, Joyce B. J. van Meurs, André G. Uitterlinden, Jenny A. Visser & John R. B. Perry
Brigham and Women’s Hospital, Boston, MA, USA
Julie E. Buring, Paul M. Ridker, Lynda M. Rose & Daniel I. Chasman
Harvard Medical School, Boston, MA, USA
Julie E. Buring, David Karasik, Paul M. Ridker & Daniel I. Chasman
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
Archie Campbell
Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
Jose E. Castelao
Institute for Maternal and Child Health – IRCCS ‘Burlo Garofolo’, Trieste, Italy
Eulalia Catamo, Martina La Bianca, Antonietta Robino & Sheila Ulivi
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Georgia Chenevix-Trench
Institute of Genetics and Biophysics – CNR, Naples, Italy
Marina Ciullo, Teresa Nutile, Daniela Ruggiero & Rossella Sorice
IRCCS Neuromed, Pozzilli, Isernia, Italy
Marina Ciullo & Daniela Ruggiero
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Fergus J. Couch
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Angela Cox
Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy
Laura Crisponi, Francesco Cucca, Antonella Mulas, Eleonora Porcu & Serena Sanna
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
Simon S. Cross
University of Sassari, Department of Biomedical Sciences, Sassari, Italy
Francesco Cucca
Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden
Kamila Czene, Per Hall & Jingmei Li
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
George Davey Smith, Deborah A. Lawlor, Susan M. Ring & Nicholas J. Timpson
Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
George Davey Smith, Deborah A. Lawlor, Susan M. Ring & Nicholas J. Timpson
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Renée de Mutsert, Dennis O. Mook-Kanamori & Frits R. Rosendaal
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
Immaculata De Vivo, Frank Hu, Peter Kraft & Meir Stampfer
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Immaculata De Vivo, Frank Hu, David Hunter & Meir Stampfer
Division of Epidemiology & Community Health, University of Minnesotta, Minneapolis, MN, USA
Ellen W. Demerath
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
Alison M. Dunning, Paul D. P. Pharoah & Douglas F. Easton
School of Life Sciences, University of Westminster, London, UK
Miriam Dwek
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Mikael Eriksson & Wei He
Population and Medical Genetics, Broad Institute, Cambridge, MA, USA
Tõnu Esko
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
Tõnu Esko, Reedik Mägi, Andres Metspalu, Lili Milani & Natalia Perjakova
David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA
Peter A. Fasching
Survey Research Center, Institute for Social Research, Ann Arbor, MI, USA
Jessica D. Faul & David R. Weir
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
Luigi Ferrucci & Toshiko Tanaka
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
Nora Franceschini & Gerardo Heiss
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
Manuela Gago-Dominguez
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
Manuela Gago-Dominguez
Department of Medical Sciences, University of Trieste, Trieste, Italy
Massimo Mezzavilla & Brumat Marco
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
Christian Gieger & Harald Grallert
Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany
Christian Gieger, Harald Grallert, Christa Meisinger, Annette Peters & Doris Stöckl
German Center for Diabetes Research (DZD), Neuherberg, Germany
Christian Gieger, Harald Grallert & Annette Peters
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
Graham G. Giles, Roger L. Milne & Melissa C. Southey
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
Graham G. Giles, John L. Hopper & Roger L. Milne
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
Graham G. Giles, Roger L. Milne & Melissa C. Southey
Icelandic Heart Association, Kopavogur, Iceland
Vilmundur Gudnason & Albert V. Smith
Faculty of Medicine, University of Iceland, Reykjavik, Iceland
Vilmundur Gudnason & Albert V. Smith
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
Pascal Guénel & Thérèse Truong
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Christopher A. Haiman
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Niclas Håkansson & Alicja Wolk
Division of Medical Oncology, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
Chunyan He
The Cancer Prevention and Control Research Program, University of Kentucky Markey Cancer Center, Lexington, KY, USA
Chunyan He
Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA
Frank Hu, David Hunter & Meir Stampfer
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
David Hunter
Broad Institute of Harvard and MIT, Cambridge, MA, USA
David Hunter
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
Mohammad A. Ikram & André G. Uitterlinden
Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
Rebecca D. Jackson
Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
Esther M. John & Allison W. Kurian
Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
Esther M. John & Allison W. Kurian
Hebrew SeniorLife Institute for Aging Research, Boston, MA, USA
David Karasik
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
Sharon L. R. Kardia, Jennifer A. Smith & Wei Zhao
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Robert Karlsson, Patrik K. E. Magnusson & Nancy L. Pedersen
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
Cari M. Kitahara & Martha Linet
Faculty of Medicine, University of Split, Split, Croatia
Ivana Kolcic
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Charles Kooperberg & Ulrike Peters
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
Peter Kraft
Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
Genevieve LaChance, Massimo Mangino, Cristina Menni & Tim D. Spector
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA
Lenore J. Launer
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, The Netherlands
Joop S. E. Laven
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
Loic Le Marchand
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Annika Lindblom
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Annika Lindblom
Department of Epidemiology, University of Washington, Seattle, WA, USA
Sara Lindstrom
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
Tricia Lindstrom & Christopher Scott
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Wake Forest, NC, USA
YongMei Liu
Department of Epidemiology, Brown University, Providence, RI, USA
Simin Liu
Department of Medicine, Brown University, Providence, RI, USA
Simin Liu
NIHR Biomedical Research Centre at Guy’s and St. Thomas’ Foundation Trust, London, UK
Massimo Mangino
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
Arto Mannermaa
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
Arto Mannermaa
Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
Arto Mannermaa
QIMR Berghofer Medical Research Insititute, Brisbane, Queensland, Australia
Nicholas G. Martin, Sarah E. Medland & Jodie N. Painter
Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany
Christa Meisinger
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Thomas Meitinger
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Grant W. Montgomery
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
Dennis O. Mook-Kanamori
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Anna M. Mulligan
Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
Anna M. Mulligan
The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK
Alison Murray
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
Mike A. Nalls
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
Anne Newman
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Anne Newman
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
Raymond Noordam
Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
Dale R. Nyholt
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
Andrew F. Olshan & Melissa A. Troester
Department of Population Science, American Cancer Society, Atlanta, GA, USA
Alpa V. Patel & Lauren R. Teras
Faculty of Medicine, University of Split, Split, Croatia
Ozren Polasek
Gen-Info Ltd, Zagreb, Croatia
Ozren Polasek
Quantify Research, Stockholm, Sweden
Iffat Rahman
Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
Gad Rennert & Hedy S. Rennert
Women’s Health Initiative Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
Jacques Rossouw
Department of Oncology, University Hospital of Larissa, Larissa, Greece
Emmanouil Saloustros
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
Dale P. Sandler
School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy’s Campus, King’s College London, London, UK
Elinor J. Sawyer
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
Chloé Sarnowski & Kathryn L. Lunetta
National Institute on Aging, Intramural Research Program, Baltimore, MD, USA
David Schlessinger
Division of Molecular Pathology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Marjanka K. Schmidt
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Marjanka K. Schmidt
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
Minouk J. Schoemaker & Anthony J. Swerdlow
Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
Katharina E. Schraut
Division of Population and Health Genomics, University of Dundee, Dundee, UK
Blair H. Smith
Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
Melissa C. Southey
Population Oncology, BC Cancer, Vancouver, British Columbia, Canada
John J. Spinelli
School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
John J. Spinelli
Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany
Doris Stöckl
Institute of Genetic Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany
Konstantin Strauch
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany
Konstantin Strauch
Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany
Konstantin Strauch
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
Anthony J. Swerdlow
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
Alexander Teumer & Henry Völzke
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
Unnur Þorsteinsdottir & Kari Stefansson
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
Celine M. Vachon
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Uwe Völker
Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Peter Vollenweider
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
Clarice R. Weinberg
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
Ko Willems van Dijk
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
Ko Willems van Dijk
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Ko Willems van Dijk
Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Bruce H. R. Wolffenbuttel
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Alicja Wolk
Department of Obstetrics and Gynecology, University Medicine Greifswald, Greifswald, Germany
Marek Zygmunt
School of Public Health, Peking University Health Science Center, Beijing, P.R. China
Liming Li
Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, P.R. China
Liming Li
Oncode Institute, Utrecht, The Netherlands
Lude Franke
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Stephen Burgess
MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
Stephen Burgess
Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
Patrick Deelen
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
Claus Yding Andersen
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Jenny Chang-Claude
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Jenny Chang-Claude
NHLBI’s and Boston University’s Framingham Heart Study, Framingham, MA, USA
Kathryn L. Lunetta & Joanne M. Murabito
Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, MA, USA
Joanne M. Murabito
Department of Paediatrics, University of Cambridge, Cambridge, UK
Ken K. Ong
Consortia
Biobank-based Integrative Omics Study (BIOS) Consortium
eQTLGen Consortium
The Biobank Japan Project
China Kadoorie Biobank Collaborative Group
kConFab Investigators
The LifeLines Cohort Study
The InterAct consortium
23andMe Research Team
(2)
InterLACE Study Team. 
Variations in reproductive events across life: a pooled analysis of data from 505 147 women across 10 countries. 
Hum. Reprod. 34, 881–893 (2019).
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Lambalk, C. B., van Disseldorp, J., de Koning, C. H. & Broekmans, F. J. 
Testing ovarian reserve to predict age at menopause. 
Maturitas 63, 280–291 (2009).
(4)
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 394, 1159–1168 (2019).
(5)
Salpeter, S. R. et al. 
Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. 
Diabetes Obes. Metab. 8, 538–554 (2006).
(6)
Manson, J. E. et al.
Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. 
J. Am. Med. Assoc. 310, 1353–1368 (2013).
(7)
Gruhn, J. R. et al. 
Chromosome errors in human eggs shape natural fertility over reproductive life span. 
Science 365, 1466–1469 (2019).
(8)
Stolk, L. et al. 
Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. 
Nat. Genet. 44, 260–268 (2012).
(9)
Venturella, R. et al. 
The genetics of non-syndromic primary ovarian insufficiency: a systematic review. 
Int. J. Fertil. Steril. 13, 161–168 (2019).
(10)
Titus, S. et al. 
Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. 
Sci. Transl. Med. 5, 172ra21 (2013).
(11)
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. 14, 1448–1459 (2000).