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

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, 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 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, Benjamin 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

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.