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

2015; Nature Portfolio; Volume: 47; Issue: 11 Linguagem: Inglês

10.1038/ng.3412

1546-1718

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 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, Gonçalo R. Abecasis, Irene L. Andrulis, Hoda Anton‐Culver, Antonis C. Antoniou, Volker Arndt, Alice M. Arnold, Caterina Barbieri, Matthias W. Beckmann, Alicia Beeghly‐Fadiel, Javier Benı́tez, Leslie Bernstein, Suzette J. Bielinski, Carl Blomqvist, Eric Boerwinkle, Natalia Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne‐Lise Børresen‐Dale, Thibaud 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 D. Figueroa, Dieter Flesch‐Janys, Ilaria Gandin, Melissa E. Garcia, Montserrat García‐Closas, Graham G. Giles, Giorgia Girotto, Mark S. Goldberg, Anna González‐Neira, Mark O. Goodarzi, Megan L. Grove, Daníel F. Guðbjartsson, 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 Kolčić, Charles Kooperberg, Veli‐Matti Kosma, Jennifer Kriebel, Vessela N. Kristensen, Diether Lambrechts, Claudia Langenberg, Jingmei Li, Xin Li, Sara Lindström, Yongmei Liu, Jian’an Luan, Jan Lubiński, Reedik Mägi, Graham J. Mann, 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 A. Nalls, Ben 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 Pirastu, Ailith Pirie, Giorgio Pistis, Ozren Polašek, David J. Porteous, Bruce M. Psaty, Katri Pylkäs, Paolo Radice, Leslie J. Raffel, Fernando Rivadeneira, Igor Rudan, Anja Rudolph, Daniela Ruggiero, Cinzia Sala, Serena Sanna, Elinor J. Sawyer, David Schlessinger, Marjanka K. Schmidt, Frank Schmidt, Rita K. Schmutzler, Minouk J. Schoemaker, Robert A. Scott, Caroline Seynaeve, Jacques Simard, Rossella Sorice, Melissa C. Southey, Doris Stöckl, Konstantin Strauch, Anthony J. Swerdlow, Kent D. Taylor, Unnur Þorsteinsdóttir, Amanda E. Toland, Ian M. Tomlinson, Thérèse Truong, Laufey Tryggvadóttír, Stephen T. Turner, Diego Vozzi, Qin Wang, Melissa Wellons, Gonneke Willemsen, James F. Wilson, Robert Winqvist, Bruce 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 Guðnason, Tim D. Spector, Cornelia M. van Duijn, Behrooz Z. Alizadeh, Marina Ciullo, Laura Crisponi, Douglas F. Easton, Paolo 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, Kári Stéfansson, Jenny A. Visser, Ken K. Ong, Jenny Chang‐Claude, Joanne M. Murabito, John R. B. Perry, Anna Murray,

Nutrition, Genetics, and Disease

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response. 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.