Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-11

AUTHORS

Felix R. Day, Katherine S. Ruth, Deborah J. Thompson, Kathryn L. Lunetta, Natalia Pervjakova, Daniel I. Chasman, Lisette Stolk, Hilary K. Finucane, Patrick Sulem, Brendan Bulik-Sullivan, Tõnu Esko, Andrew D. Johnson, Cathy E. Elks, Nora Franceschini, Chunyan He, Elisabeth Altmaier, Jennifer A. Brody, Lude L. Franke, Jennifer E. Huffman, Margaux F. Keller, Patrick F. McArdle, Teresa Nutile, Eleonora Porcu, Antonietta Robino, Lynda M. Rose, Ursula M. Schick, Jennifer A. Smith, Alexander Teumer, Michela Traglia, Dragana Vuckovic, Jie Yao, Wei Zhao, Eva Albrecht, Najaf Amin, Tanguy Corre, Jouke-Jan Hottenga, Massimo Mangino, Albert V. Smith, Toshiko Tanaka, Goncalo Abecasis, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Volker Arndt, Alice M. Arnold, Caterina Barbieri, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Leslie Bernstein, Suzette J. Bielinski, Carl Blomqvist, Eric Boerwinkle, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne-Lise Borresen-Dale, Thibaud S Boutin, Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Archie Campbell, Harry Campbell, Stephen J. Chanock, J. Ross Chapman, Yii-Der Ida Chen, Georgia Chenevix-Trench, Fergus J. Couch, Andrea D. Coviello, Angela Cox, Kamila Czene, Hatef Darabi, Immaculata De Vivo, Ellen W. Demerath, Joe Dennis, Peter Devilee, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, John D. Eicher, Peter A. Fasching, Jessica D. Faul, Jonine Figueroa, Dieter Flesch-Janys, Ilaria Gandin, Melissa E. Garcia, Montserrat García-Closas, Graham G. Giles, Giorgia G. Girotto, Mark S. Goldberg, Anna González-Neira, Mark O. Goodarzi, Megan L. Grove, Daniel F. Gudbjartsson, Pascal Guénel, Xiuqing Guo, Christopher A. Haiman, Per Hall, Ute Hamann, Brian E. Henderson, Lynne J. Hocking, Albert Hofman, Georg Homuth, Maartje J. Hooning, John L. Hopper, Frank B. Hu, Jinyan Huang, Keith Humphreys, David J. Hunter, Anna Jakubowska, Samuel E. Jones, Maria Kabisch, David Karasik, Julia A. Knight, Ivana Kolcic, Charles Kooperberg, Veli-Matti Kosma, Jennifer Kriebel, Vessela Kristensen, Diether Lambrechts, Claudia Langenberg, Jingmei Li, Xin Li, Sara Lindström, Yongmei Liu, Jian’an Luan, Jan Lubinski, Reedik Mägi, Arto Mannermaa, Judith Manz, Sara Margolin, Jonathan Marten, Nicholas G. Martin, Corrado Masciullo, Alfons Meindl, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L. Milne, Martina Müller-Nurasyid, Michael Nalls, Ben M. Neale, Heli Nevanlinna, Patrick Neven, Anne B. Newman, Børge G. Nordestgaard, Janet E. Olson, Sandosh Padmanabhan, Paolo Peterlongo, Ulrike Peters, Astrid Petersmann, Julian Peto, Paul D.P. Pharoah, Nicola N. Pirastu, Ailith Pirie, Giorgio Pistis, Ozren Polasek, David Porteous, Bruce M. Psaty, Katri Pylkäs, Paolo Radice, Leslie J. Raffel, Fernando Rivadeneira, Igor Rudan, Anja Rudolph, Daniela Ruggiero, Cinzia F. Sala, Serena Sanna, Elinor J. Sawyer, David Schlessinger, Marjanka K. Schmidt, Frank Schmidt, Rita K. Schmutzler, Minouk J. Schoemaker, Robert A. Scott, Caroline M. Seynaeve, Jacques Simard, Rossella Sorice, Melissa C. Southey, Doris Stöckl, Konstantin Strauch, Anthony Swerdlow, Kent D. Taylor, Unnur Thorsteinsdottir, Amanda E. Toland, Ian Tomlinson, Thérèse Truong, Laufey Tryggvadottir, Stephen T. Turner, Diego Vozzi, Qin Wang, Melissa Wellons, Gonneke Willemsen, James F. Wilson, Robert Winqvist, Bruce B.H.R. Wolffenbuttel, Alan F. Wright, Drakoulis Yannoukakos, Tatijana Zemunik, Wei Zheng, Marek Zygmunt, Sven Bergmann, Dorret I. Boomsma, Julie E. Buring, Luigi Ferrucci, Grant W. Montgomery, Vilmundur Gudnason, Tim D. Spector, Cornelia M van Duijn, Behrooz Z. Alizadeh, Marina Ciullo, Laura Crisponi, Douglas F. Easton, Paolo P. Gasparini, Christian Gieger, Tamara B. Harris, Caroline Hayward, Sharon L.R. Kardia, Peter Kraft, Barbara McKnight, Andres Metspalu, Alanna C. Morrison, Alex P. Reiner, Paul M. Ridker, Jerome I. Rotter, Daniela Toniolo, André G. Uitterlinden, Sheila Ulivi, Henry Völzke, Nicholas J. Wareham, David R. Weir, Laura M. Yerges-Armstrong, , , , , , , Alkes L. Price, Kari Stefansson, Jenny A. Visser, Ken K. Ong, Jenny Chang-Claude, Joanne M. Murabito, John R.B. Perry, Anna Murray

ABSTRACT

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms. More... »

PAGES

1294-1303

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    11

    VOLUME

    47

    Author Affiliations

  • University of Cambridge
  • University of Exeter
  • Boston University
  • University of Tartu
  • Harvard University
  • Erasmus University Medical Center
  • Massachusetts Institute of Technology
  • Broad Institute
  • University of North Carolina System
  • Indiana University – Purdue University Indianapolis
  • Helmholtz Zentrum München
  • University of Washington
  • University of Edinburgh
  • University of Maryland, Baltimore
  • Institute of Genetics and Biophysics
  • University of Sassari
  • IRCCS Materno Infantile Burlo Garofolo
  • Brigham and Women's Hospital
  • Fred Hutchinson Cancer Research Center
  • University of Michigan–Ann Arbor
  • University of Greifswald
  • San Raffaele Hospital
  • University of Trieste
  • Harbor–UCLA Medical Center
  • Swiss Institute of Bioinformatics
  • VU University Amsterdam
  • National Institute for Health Research
  • University of Iceland
  • National Institute on Aging
  • University of Toronto
  • University of California, Irvine
  • German Cancer Research Center
  • Spanish National Cancer Research Centre
  • City Of Hope National Medical Center
  • Mayo Clinic
  • Helsinki University Central Hospital
  • Baylor College of Medicine
  • Hannover Medical School
  • University of Copenhagen
  • University of Oslo
  • Ruhr University Bochum
  • Heidelberg University
  • National Cancer Institute
  • Wellcome Centre for Human Genetics
  • QIMR Berghofer Medical Research Institute
  • Boston University School of Medicine
  • University of Sheffield
  • Karolinska Institute
  • Leiden University Medical Center
  • London School of Hygiene & Tropical Medicine
  • University of California Los Angeles
  • University Medical Center Hamburg-Eppendorf
  • Institute of Cancer Research
  • Cancer Council Victoria
  • McGill University
  • Cedars-Sinai Medical Center
  • The University of Texas Health Science Center at Houston
  • University of Paris-Sud
  • University of Southern California
  • University of Aberdeen
  • University of Melbourne
  • Shanghai Jiao Tong University
  • Pomeranian Medical University
  • University of Split
  • Kuopio University Hospital
  • German Center for Diabetes Research
  • KU Leuven
  • Technical University Munich
  • German Centre for Cardiovascular Research
  • University of Pittsburgh
  • University of Glasgow
  • FIRC Institute of Molecular Oncology
  • University of Oulu
  • Istituto Nazionale dei Tumori
  • National Research Council
  • King's College London
  • Antoni van Leeuwenhoek Hospital
  • University Hospital Cologne
  • Université Laval
  • Ludwig Maximilian University of Munich
  • The Ohio State University
  • Churchill Hospital
  • Vanderbilt University Medical Center
  • National Centre of Scientific Research Demokritos
  • University Medical Center Groningen
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ng.3412

    DOI

    http://dx.doi.org/10.1038/ng.3412

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1026125304

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26414677


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