| Literature DB >> 34349265 |
Katherine S Ruth1, Felix R Day2, Jazib Hussain3, Ana Martínez-Marchal4,5, Catherine E Aiken6,7, Ajuna Azad3, Deborah J Thompson8, Lucie Knoblochova9,10, Hironori Abe11, Jane L Tarry-Adkins6,7, Javier Martin Gonzalez12, Pierre Fontanillas13, Annique Claringbould14, Olivier B Bakker15, Patrick Sulem16, Robin G Walters17,18, Chikashi Terao19,20,21, Sandra Turon22, Momoko Horikoshi23, Kuang Lin17, N Charlotte Onland-Moret24, Aditya Sankar3, Emil Peter Thrane Hertz3,25, Pascal N Timshel26, Vallari Shukla3, Rehannah Borup3, Kristina W Olsen3,27, Paula Aguilera3,28, Mònica Ferrer-Roda4,5, Yan Huang4,5, Stasa Stankovic2, Paul R H J Timmers29,30, Thomas U Ahearn31, Behrooz Z Alizadeh32, Elnaz Naderi32, Irene L Andrulis33,34, Alice M Arnold35, Kristan J Aronson36,37, Annelie Augustinsson38, Stefania Bandinelli39, Caterina M Barbieri40, Robin N Beaumont1, Heiko Becher41, Matthias W Beckmann42, Stefania Benonisdottir16, Sven Bergmann43,44, Murielle Bochud45, Eric Boerwinkle46, Stig E Bojesen47,48,49, Manjeet K Bolla8, Dorret I Boomsma50,51,52, Nicholas Bowker2, Jennifer A Brody53, Linda Broer54, Julie E Buring55,56, Archie Campbell57, Harry Campbell29, Jose E Castelao58, Eulalia Catamo59, Stephen J Chanock31, Georgia Chenevix-Trench60, Marina Ciullo61,62, Tanguy Corre43,44,45, Fergus J Couch63, Angela Cox64, Laura Crisponi65, Simon S Cross66, Francesco Cucca65,67, Kamila Czene68, George Davey Smith69,70, Eco J C N de Geus50,51,52, Renée de Mutsert71, Immaculata De Vivo72,73, Ellen W Demerath74, Joe Dennis8, Alison M Dunning75, Miriam Dwek76, Mikael Eriksson77, Tõnu Esko78,79, Peter A Fasching42,80, Jessica D Faul81, Luigi Ferrucci82, Nora Franceschini83, Timothy M Frayling1, Manuela Gago-Dominguez84,85, Massimo Mezzavilla86, Montserrat García-Closas31, Christian Gieger87,88,89, Graham G Giles90,91,92, Harald Grallert87,88,89, Daniel F Gudbjartsson16, Vilmundur Gudnason93,94, Pascal Guénel95, Christopher A Haiman96, Niclas Håkansson97, Per Hall68, Caroline Hayward30, Chunyan He98,99, Wei He77, Gerardo Heiss83, Miya K Høffding3, John L Hopper91, Jouke J Hottenga50,51,52, Frank Hu72,73,100, David Hunter17,73,100,72,101, Mohammad A Ikram102, Rebecca D Jackson103, Micaella D R Joaquim1, Esther M John104,105, Peter K Joshi29, David Karasik56,106, Sharon L R Kardia107, Christiana Kartsonaki17,18, Robert Karlsson77, Cari M Kitahara108, Ivana Kolcic109, Charles Kooperberg110, Peter Kraft72,111, Allison W Kurian104,105, Zoltan Kutalik44,45, Martina La Bianca59, Genevieve LaChance112, Claudia Langenberg2, Lenore J Launer113, Joop S E Laven114, Deborah A Lawlor69,70, Loic Le Marchand115, Jingmei Li68, Annika Lindblom116,117, Sara Lindstrom118, Tricia Lindstrom119, Martha Linet108, YongMei Liu120, Simin Liu121,122, Jian'an Luan2, Reedik Mägi79, Patrik K E Magnusson77, Massimo Mangino112,123, Arto Mannermaa124,125,126, Brumat Marco86, Jonathan Marten30, Nicholas G Martin127, Hamdi Mbarek50,51,52, Barbara McKnight35, Sarah E Medland127, Christa Meisinger88,128, Thomas Meitinger129, Cristina Menni112, Andres Metspalu79, Lili Milani79, Roger L Milne90,91,92, Grant W Montgomery130, Dennis O Mook-Kanamori71,131, Antonella Mulas65, Anna M Mulligan132,133, Alison Murray134, Mike A Nalls135, Anne Newman136,137, Raymond Noordam138, Teresa Nutile61, Dale R Nyholt139, Andrew F Olshan140, Håkan Olsson38, Jodie N Painter127, Alpa V Patel141, Nancy L Pedersen77, Natalia Perjakova79, Annette Peters88,89, Ulrike Peters110, Paul D P Pharoah8,75, Ozren Polasek109,142, Eleonora Porcu65, Bruce M Psaty53, Iffat Rahman143, Gad Rennert144, Hedy S Rennert144, Paul M Ridker55,56, Susan M Ring69,70, Antonietta Robino59, Lynda M Rose55, Frits R Rosendaal71, Jacques Rossouw145, Igor Rudan29, Rico Rueedi43,44, Daniela Ruggiero61,62, Cinzia F Sala40, Emmanouil Saloustros146, Dale P Sandler147, Serena Sanna65, Elinor J Sawyer148, Chloé Sarnowski149, David Schlessinger150, Marjanka K Schmidt151,152, Minouk J Schoemaker153, Katharina E Schraut29,154, Christopher Scott119, Saleh Shekari1, Amruta Shrikhande3, Albert V Smith93,94, Blair H Smith155, Jennifer A Smith107, Rossella Sorice61, Melissa C Southey90,92,156, Tim D Spector112, John J Spinelli157,158, Meir Stampfer72,73,100, Doris Stöckl88,159, Joyce B J van Meurs54, Konstantin Strauch160,161,162, Unnur Styrkarsdottir16, Anthony J Swerdlow153,163, Toshiko Tanaka82, Lauren R Teras141, Alexander Teumer164, Unnur Þorsteinsdottir16,165, Nicholas J Timpson69,70, Daniela Toniolo40, Michela Traglia40, Melissa A Troester140, Thérèse Truong95, Jessica Tyrrell1, André G Uitterlinden54,102, Sheila Ulivi59, Celine M Vachon166, Veronique Vitart30, Uwe Völker167, Peter Vollenweider168, Henry Völzke164, Qin Wang8, Nicholas J Wareham2, Clarice R Weinberg169, David R Weir81, Amber N Wilcox31, Ko Willems van Dijk170,171,172, Gonneke Willemsen50,51,52, James F Wilson29,30, Bruce H R Wolffenbuttel173, Alicja Wolk97,174, Andrew R Wood1, Wei Zhao107, Marek Zygmunt175, Zhengming Chen17,18, Liming Li176,177, Lude Franke15,178, Stephen Burgess179,180, Patrick Deelen15,181, Tune H Pers26, Marie Louise Grøndahl27, Claus Yding Andersen182, Anna Pujol22, Andres J Lopez-Contreras3,28, Jeremy A Daniel25, Kari Stefansson16,165, Jenny Chang-Claude183,184, Yvonne T van der Schouw24, Kathryn L Lunetta149,185, Daniel I Chasman55,56, Douglas F Easton8,75, Jenny A Visser54, Susan E Ozanne6, Satoshi H Namekawa11, Petr Solc9, Joanne M Murabito185,186, Ken K Ong2,187, Eva R Hoffmann188, Anna Murray189, Ignasi Roig190,191, John R B Perry192,193.
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.Entities:
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Year: 2021 PMID： 34349265 PMCID： PMC7611832 DOI： 10.1038/s41586-021-03779-7
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 69.504