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Genetic insights into the biological mechanisms governing human ovarian ageing

Authors :
Unnur Styrkarsdottir
Daniel I. Chasman
Rehannah Borup
Anne B. Newman
Kristina W. Olsen
Lude Franke
Stefania Bandinelli
Nora Franceschini
Celine M. Vachon
Nicholas J. Timpson
James F. Wilson
Micaella Joaquim
Christa Meisinger
Felix R. Day
Charles Kooperberg
Qin Wang
Pascal Timshel
Dennis O. Mook-Kanamori
Luigi Ferrucci
Jennifer A. Smith
Miriam Dwek
Pascal Guénel
Claus Yding Andersen
Peter A. Fasching
Sven Bergmann
Thomas Meitinger
Nicholas Bowker
Jane L. Tarry-Adkins
Jeremy A. Daniel
Katharina E. Schraut
Mikael Eriksson
Amruta Shrikhande
Jacques E. Rossouw
Amber N. Wilcox
Simon S. Cross
Stasa Stankovic
Montserrat Garcia-Closas
Mohammad Arfan Ikram
Annette Peters
David Schlessinger
Sheila Ulivi
Mònica Ferrer-Roda
Immaculata De Vivo
Michela Traglia
Jessica Tyrrell
Paul R. H. J. Timmers
Rico Rueedi
Ko Willems van Dijk
N. Charlotte Onland-Moret
Doris Stöckl
Anthony J. Swerdlow
Paul M. Ridker
Zoltán Kutalik
Patrick Deelen
Gerardo Heiss
Marie Louise Grøndahl
Alison M. Dunning
Dale R. Nyholt
Nicholas J. Wareham
Reedik Mägi
Stephen J. Chanock
Martina La Bianca
Ozren Polasek
Daniel F. Gudbjartsson
Rebecca D. Jackson
Alison D. Murray
Lynda M. Rose
Hironori Abe
Joanne M. Murabito
Henry Völzke
Daniela Ruggiero
Dorret I. Boomsma
Harald Grallert
Stefania Benonisdottir
Javier Martin Gonzalez
Esther M. John
Natalia Perjakova
Georgia Chenevix-Trench
John R. B. Perry
Jenny Chang-Claude
Archie Campbell
Teresa Nutile
Ellen W. Demerath
Robin N Beaumont
Jouke J. Hottenga
Albert V. Smith
David Karasik
Linda Broer
Raymond Noordam
Wei He
Niclas Håkansson
Catherine E. Aiken
Robert Karlsson
Christopher A. Haiman
Massimo Mangino
Melissa C. Southey
Sharon L.R. Kardia
Nicholas G. Martin
Jodie N. Painter
Peter K. Joshi
Gonneke Willemsen
Lenore J. Launer
Alicja Wolk
Konstantin Strauch
Stig E. Bojesen
Manjeet K. Bolla
Allison W. Kurian
Renée de Mutsert
Joop S.E. Laven
Antonella Mulas
Igor Rudan
Vallari Shukla
Kathyrn L Lunetta
Susan E. Ozanne
Loic Le Marchand
Jenny A. Visser
Gad Rennert
Jennifer A. Brody
Paul D.P. Pharoah
Tune H. Pers
Sara Lindström
Ignasi Roig
Angela Cox
Unnur Þorsteinsdottir
Graham G. Giles
Toshiko Tanaka
Eva Hoffmann
Melissa A. Troester
Claudia Langenberg
Serena Sanna
Julie E. Buring
Anna Pujol
Mike A. Nalls
Kamila Czene
Tõnu Esko
Jian'an Luan
Lili Milani
Iffat Rahman
Sarah E. Medland
Caterina Barbieri
Emil Peter Trane Hertz
Behrooz Z. Alizadeh
David G. Hunter
Sandra Turon
Antonietta Robino
Marina Ciullo
Barbara McKnight
Chunyan He
Bruce H. R. Wolffenbuttel
David R. Weir
Daniela Toniolo
Ulrike Peters
George Davey-Smith
Saleh Shekari
Caroline Hayward
Elinor J. Sawyer
Patrick Sulem
Simin Liu
Tanguy Corre
Susan M. Ring
Peter Kraft
Alexander Teumer
Marjanka K. Schmidt
André G. Uitterlinden
Arto Mannermaa
Kristan J. Aronson
Heiko Becher
John L. Hopper
Alpa V. Patel
Joyce B. J. van Meurs
kConFab Investigators
Hamdi Mbarek
Frits R. Rosendaal
Minouk J. Schoemaker
Satoshi H. Namekawa
Miya Kudo Høffding
Fergus J. Couch
Nancy L. Pedersen
Jessica D. Faul
Patrik K. E. Magnusson
Jingmei Li
Christopher G. Scott
Joe Dennis
Genevieve Lachance
Ajuna Azad
Yongmei Liu
Elnaz Naderi
Andrew R. Wood
Yan Huang
Anna Murray
Annique Claringbould
Stephen Burgess
Jose E. Castelao
Brumat Marco
Eco J. C. de Geus
Veronique Vitart
Ken K. Ong
Kari Stefansson
Blair H. Smith
Francesco Cucca
Grant W. Montgomery
Emmanouil Saloustros
Andrés J. López-Contreras
Jonathan Marten
Håkan Olsson
Dale P. Sandler
Alice M. Arnold
Ana Martínez-Marchal
Tim D. Spector
Chloé Sarnowski
John J. Spinelli
Vilmundur Gudnason
Frank B. Hu
Thomas U. Ahearn
Hedy S. Rennert
Olivier B. Bakker
Eric Boerwinkle
Matthias W. Beckmann
Jazib Hussain
Uwe Völker
Peter Vollenweider
Douglas F. Easton
Irene L. Andrulis
Harry Campbell
Manuela Gago-Dominguez
Cari M. Kitahara
Yvonne T. van der Schouw
Eleonora Porcu
Annika Lindblom
Martha S. Linet
Meir J. Stampfer
Eulalia Catamo
Roger L. Milne
Ivana Kolcic
Annelie Augustinsson
Cinzia Sala
Debbie A Lawlor
Cristina Menni
Timothy M. Frayling
Lauren R. Teras
Marek Zygmunt
Tricia Lindstrom
Clarice R. Weinberg
Bruce M. Psaty
Thérèse Truong
Anna Marie Mulligan
Deborah J. Thompson
Per Hall
Rossella Sorice
Wei Zhao
Andres Metspalu
Katherine S. Ruth
Andrew F. Olshan
Massimo Mezzavilla
Murielle Bochud
Christian Gieger
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

Abstract

Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the 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 ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenicFMR1premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR 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 increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........b18fc43cd9f16417f22121a8650074ef