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Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair

2015; Lippincott Williams & Wilkins; Volume: 70; Issue: 12 Linguagem: Inglês

10.1097/01.ogx.0000473766.71624.99

1533-9866

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, 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 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 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,

Sex and Gender in Healthcare

Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays. This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach. Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P = 3 × 10−14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDR mechanisms. This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDR genes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.