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Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

2015; Nature Portfolio; Volume: 47; Issue: 4 Linguagem: Inglês

10.1038/ng.3242

1546-1718

Kyriaki Michailidou, Jonathan Beesley, Sara Lindström, Sander Canisius, Joe Dennis, Michael Lush, Mel Maranian, Manjeet K. Bolla, Sophia Wang, Mitul Shah, Barbara Perkins, Kamila Czene, Mikael Eriksson, Hatef Darabi, Judith S. Brand, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, Sune F. Nielsen, Nazneen Rahman, Clare Turnbull, Olivia Fletcher, Julian Peto, Lorna J. Gibson, Isabel dos‐Santos‐Silva, Jenny Chang‐Claude, Dieter Flesch‐Janys, Anja Rudolph, Ursula Eilber, Sabine Behrens, Heli Nevanlinna, Taru Muranen, Kristiina Aittomäki, Carl Blomqvist, Sofia Khan, Kirsimari Aaltonen, Habibul Ahsan, Muhammad G. Kibriya, Alice S. Whittemore, Esther M. John, Kathleen E. Malone, Marilie D. Gammon, Regina M. Santella, Giske Ursin, Enes Makalic, Daniel F. Schmidt, Graham Casey, David J. Hunter, Susan M. Gapstur, Mia M. Gaudet, W. Ryan Diver, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Loı̈c Le Marchand, Christine D. Berg, Stephen J. Chanock, Jonine D. Figueroa, Robert N. Hoover, Diether Lambrechts, Patrick Neven, Hans Wildiers, Erik Van Limbergen, Marjanka K. Schmidt, Annegien Broeks, Senno Verhoef, Sten Cornelissen, Fergus J. Couch, Janet E. Olson, Emily Hallberg, Celine M. Vachon, Quinten Waisfisz, Hanne Meijers‐Heijboer, Muriel A. Adank, Rob B. van der Luijt, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji‐Yeob Choi, Sue K. Park, Keun-Young Yoo, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Pascal Guénel, Thérèse Truong, Claire Mulot, Marie-Pierre Sanchez, Barbara Burwinkel, Frederik Marmé, Harald Surowy, Christof Sohn, Anna H. Wu, Chiu-Chen Tseng, David Van Den Berg, Daniel O. Stram, Anna González‐Neira, Javier Benı́tez, M. Pilar Zamora, José Ignacio Arias Pérez, Xiao‐Ou Shu, Wei Lu, Yu‐Tang Gao, Hui Cai, Angela Cox, Simon S. Cross, Malcolm Reed, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Annika Lindblom, Sara Margolin, Soo‐Hwang Teo, Cheng Har Yip, Nur Aishah Mohd Taib, Gie-Hooi Tan, Maartje J. Hooning, Antoinette Hollestelle, John W.M. Martens, J. Margriet Collée, William J. Blot, Lisa B. Signorello, Qiuyin Cai, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Carmel Apicella, Chen‐Yang Shen, Chia‐Ni Hsiung, Pei‐Ei Wu, Ming‐Feng Hou, Vessela N. Kristensen, Silje Nord, Grethe I.G. Alnæs, Graham G. Giles, Roger L. Milne, Catriona McLean, Federico Canzian, Dimitrios Trichopoulos, Petra H. Peeters, Eiliv Lund, Malin Sund, Kay‐Tee Khaw, Marc J. Gunter, Domenico Palli, Lotte Maxild Mortensen, Laure Dossus, José María Huerta, Alfons Meindl, Rita K. Schmutzler, Christian Sutter, Rongxi Yang, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart‐Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Kee Seng Chia, Ching Wan Chan, Peter A. Fasching, Alexander Hein, Matthias W. Beckmann, Lothar Haeberle, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Anthony J. Swerdlow, Louise A. Brinton, Montserrat García‐Closas, Wei Zheng, Sandra L. Halverson, Martha J. Shrubsole, Jirong Long, Mark S. Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola‐Vuorinen, Mervi Grip, Hiltrud Brauch, Ute Hamann, Thomas Brüning, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Natalia Bogdanova, Thilo Dörk, Graham J. Mann, Vesa Kataja, Veli‐Matti Kosma, Jaana M. Hartikainen, Peter Devilee, Robert A.E.M. Tollenaar, Caroline Seynaeve, Christi J. van Asperen, Anna Jakubowska, Jan Lubiński, Katarzyna Jaworska, Tomasz Huzarski, Suleeporn Sangrajrang, Valérie Gaborieau, Paul Brennan, James McKay, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Maria Kabisch, Diana Torres, Susan L. Neuhausen, Hoda Anton‐Culver, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Catherine S. Healey, Daniel C. Tessier, Daniel Vincent, François Bacot, Guillermo Pita, M. Rosario Alonso, Núria Álvarez, Daniel Herrero, Jacques Simard, Paul D.P. Pharoah, Peter Kraft, Alison M. Dunning, Georgia Chenevix‐Trench, Per Hall, Douglas F. Easton,

Genomics and Chromatin Dynamics

Doug Easton and colleagues report the results of a large-scale genome-wide association study of breast cancer. They discover 15 new susceptibility loci and highlight likely target genes in several of the newly associated regions. Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10−8. Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.