Genetic insights into biological mechanisms governing human ovarian ageing

Autor: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem
Přispěvatelé: Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Gerontology
Aging
Far East
Endocrinology
Diabetes and Metabolism
Menopause
Premature
Genome-wide association study
VARIANTS
Primary Ovarian Insufficiency
Inbred C57BL
Bioinformatics
DISEASE
Healthy Aging
genetics of ovarian aging
Fragile X Mental Retardation Protein
Mice
Endocrinology
Medicine
EARLY MENOPAUSE
media_common
RISK
Multidisciplinary
Asia
Eastern
Reproduction
Longevity
Middle Aged
Europe
MENDELIAN RANDOMIZATION
Medical genetics
Female
ICEP
Menopause
Adult
Alleles
Animals
Bone and Bones
Checkpoint Kinase 1
Checkpoint Kinase 2
Diabetes Mellitus
Type 2
Diet
Fertility
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Mice
Inbred C57BL
Ovary
Uterus
Type 2
medicine.medical_specialty
media_common.quotation_subject
MEDLINE
Biology
Premature ovarian insufficiency
Article
genome-wide meta-analysis
SDG 3 - Good Health and Well-being
GERMLINE
Diabetes Mellitus
Genetic predisposition
Ovarian reserve
Premature
business.industry
Human genetics
CHROMOSOME SYNAPSIS
DNA-DAMAGE
Ageing
EXPRESSION ANALYSIS
business
MEIOTIC CELL-CYCLE
Zdroj: University of Bristol-PURE
Nature, 596(7872), 393-397. NATURE PORTFOLIO
Nature 596, 393-397 (2021)
Nature, 596(7872), 393-397. Nature Publishing Group
Nature (Lond.) 596 (2021): 393–397. doi:10.1038/s41586-021-03779-7
info:cnr-pdr/source/autori:Ruth K.S.; Day F.R.; Hussain J.; Martinez-Marchal A.; Aiken C.E.; Azad A.; Thompson D.J.; Knoblochova L.; Abe H.; Tarry-Adkins J.L.; Gonzalez J.M.; Fontanillas P.; Claringbould A.; Bakker O.B.; Sulem P.; Walters R.G.; Terao C.; Turon S.; Horikoshi M.; Lin K.; Onland-Moret N.C.; Sankar A.; Hertz E.P.T.; Timshel P.N.; Shukla V.; Borup R.; Olsen K.W.; Aguilera P.; Ferrer-Roda M.; Huang Y.; Stankovic S.; Timmers P.R.H.J.; Ahearn T.U.; Alizadeh B.Z.; Naderi E.; Andrulis I.L.; Arnold A.M.; Aronson K.J.; Augustinsson A.; Bandinelli S.; Barbieri C.M.; Beaumont R.N.; Becher H.; Beckmann M.W.; Benonisdottir S.; Bergmann S.; Bochud M.; Boerwinkle E.; Bojesen S.E.; Bolla M.K.; Boomsma D.I.; Bowker N.; Brody J.A.; Broer L.; Buring J.E.; Campbell A.; Campbell H.; Castelao J.E.; Catamo E.; Chanock S.J.; Chenevix-Trench G.; Ciullo M.; Corre T.; Couch F.J.; Cox A.; Crisponi L.; Cross S.S.; Cucca F.; Czene K.; Smith G.D.; de Geus E.J.C.N.; de Mutsert R.; De Vivo I.; Demerath E.W.; Dennis J.; Dunning A.M.; Dwek M.; Eriksson M.; Esko T.; Fasching P.A.; Faul J.D.; Ferrucci L.; Franceschini N.; Frayling T.M.; Gago-Dominguez M.; Mezzavilla M.; Garcia-Closas M.; Gieger C.; Giles G.G.; Grallert H.; Gudbjartsson D.F.; Gudnason V.; Guenel P.; Haiman C.A.; Hakansson N.; Hall P.; Hayward C.; He C.; He W.; Heiss G.; Hoffding M.K.; Hopper J.L.; Hottenga J.J.; Hu F.; Hunter D.; Ikram M.A.; Jackson R.D.; Joaquim M.D.R.; John E.M.; Joshi P.K.; Karasik D.; Kardia S.L.R.; Kartsonaki C.; Karlsson R.; Kitahara C.M.; Kolcic I.; Kooperberg C.; Kraft P.; Kurian A.W.; Kutalik Z.; La Bianca M.; LaChance G.; Langenberg C.; Launer L.J.; Laven J.S.E.; Lawlor D.A.; Le Marchand L.; Li J.; Lindblom A.; Lindstrom S.; Lindstrom T.; Linet M.; Liu Y.M.; Liu S.; Luan J.; Magi R.; Magnusson P.K.E.; Mangino M.; Mannermaa A.; Marco B.; Marten J.; Martin N.G.; Mbarek H.; McKnight B.; Medland S.E.; Meisinger C.; Meitinger T.; Menni C.; Metspalu A.; Milani L.; Milne R.L.; Montgomery G.W.; Mook-Kanamori D.O.; Mulas A.; Mulligan A.M.; Murray A.; Nalls M.A.; Newman A.; Noordam R.; Nutile T.; Nyholt D.R.; Olshan A.F.; Olsson H.; Painter J.N.; Patel A.V.; Pedersen N.L.; Perjakova N.; Peters A.; Peters U.; Pharoah P.D.P.; Polasek O.; Porcu E.; Psaty B.M.; Rahman I.; Rennert G.; Rennert H.S.; Ridker P.M.; Ring S.M.; Robino A.; Rose L.M.; Rosendaal F.R.; Rossouw J.; Rudan I.; Rueedi R.; Ruggiero D.; Sala C.F.; Saloustros E.; Sandler D.P.; Sanna S.; Sawyer E.J.; Sarnowski C.; Schlessinger D.; Schmidt M.K.; Schoemaker M.J.; Schraut K.E.; Scott C.; Shekari S.; Shrikhande A.; Smith A.V.; Smith B.H.; Smith J.A.; Sorice R.; Southey M.C.; Spector T.D.; Spinelli J.J.; Stampfer M.; Stockl D.; van Meurs J.B.J.; Strauch K.; Styrkarsdottir U.; Swerdlow A.J.; Tanaka T.; Teras L.R.; Teumer A.; Thorsteinsdottir U.; Timpson N.J.; Toniolo D.; Traglia M.; Troester M.A.; Truong T.; Tyrrell J.; Uitterlinden A.G.; Ulivi S.; Vachon C.M.; Vitart V.; Volker U.; Vollenweider P.; Volzke H.; Wang Q.; Wareham N.J.; Weinberg C.R.; Weir D.R.; Wilcox A.N.; van Dijk K.W.; Willemsen G.; Wilson J.F.; Wolffenbuttel B.H.R.; Wolk A.; Wood A.R.; Zhao W.; Zygmunt M.; Chen Z.; Li L.; Franke L.; Burgess S.; Deelen P.; Pers T.H.; Grondahl M.L.; Andersen C.Y.; Pujol A.; Lopez-Contreras A.J.; Daniel J.A.; Stefansson K.; Chang-Claude J.; van der Schouw Y.T.; Lunetta K.L.; Chasman D.I.; Easton D.F.; Visser J.A.; Ozanne S.E.; Namekawa S.H.; Solc P.; Murabito J.M.; Ong K.K.; Hoffmann E.R.; Murray A.; Roig I.; Perry J.R.B./titolo:Genetic insights into biological mechanisms governing human ovarian ageing/doi:10.1038%2Fs41586-021-03779-7/rivista:Nature (Lond.)/anno:2021/pagina_da:393/pagina_a:397/intervallo_pagine:393–397/volume:596
Digital.CSIC. Repositorio Institucional del CSIC
instname
Nature
Ruth, K S, Day, F R, Hussain, J, Martinez-Marchal, A, Aiken, C E, Azad, A, Thompson, D J, Knoblochova, L, Abe, H, Tarry-Adkins, J L, Gonzalez, J M, Fontanillas, P, Claringbould, A, Bakker, O B, Sulem, P, Walters, R G, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, N C, Sankar, A, Hertz, E P T, Timshel, P N, Shukla, V, Borup, R, Olsen, K W, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, P R H J, Ahearn, T U, Alizadeh, B Z, Naderi, E, Andrulis, I L, Arnold, A M, Aronson, K J, Augustinsson, A, Bojesen, S E, Hoffding, M K, Shrikhande, A, Pers, T H, Grøndahl, M L, Andersen, C Y, Lopez-Contreras, A J, Daniel, J A, Hoffmann, E R, Biobank-based Integrative Omics St, eQTLGen Consortium, BioBank Japan Project, China Kadoorie Biobank Collaborati, kConFab Investigators, LifeLines Cohort Study, InterAct Consortium & 23 Me Res Team 2021, ' Genetic insights into biological mechanisms governing human ovarian ageing ', Nature, vol. 596, pp. 393-397 . https://doi.org/10.1038/s41586-021-03779-7
Ruth, K S, Davey Smith, G, Lawlor, D A, Ring, S M, Timpson, N J, Perry, J R B & al., E 2021, ' Genetic insights into biological mechanisms governing human ovarian ageing ', Nature . https://doi.org/10.1038/s41586-021-03779-7
Ruth, K S, Boomsma, D I, de Geus, E J C N, Hottenga, J J, Willemsen, G, Murray, A, Perry, J R B, China Kadoorie Biobank Collaborative Group, kConFab Investigators, The LifeLines Cohort Study, The InterAct consortium, 23Andme Research Team, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium & The Biobank Japan Project 2021, ' Genetic insights into biological mechanisms governing human ovarian ageing ', Nature, vol. 596, no. 7872, pp. 393-397 . https://doi.org/10.1038/s41586-021-03779-7
2021, ' Genetic insights into biological mechanisms governing human ovarian ageing ', Nature . https://doi.org/10.1038/s41586-021-03779-7
ISSN: 0028-0836
DOI: 10.1038/s41586-021-03779-7
Popis: 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.
Databáze: OpenAIRE
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