Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Roger L Milne, Karoline B Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindström, Shirley Hui, Audrey Lemaçon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K Bolla, Lesley McGuffog, Qin Wang, Cora M Aalfs, Marcia Adams, Julian Adlard, Simona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Aittomäki, Fares Al-Ejeh, Jamie Allen, Christine B Ambrosone, Christopher I Amos, Irene L Andrulis, Hoda Anton-Culver, Natalia N Antonenkova, Volker Arndt, Norbert Arnold, Kristan J Aronson, Bernd Auber, Paul L Auer, Margreet G E M Ausems, Jacopo Azzollini, François Bacot, Judith Balmaña, Monica Barile, Laure Barjhoux, Rosa B Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W Beckmann, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Yves-Jean Bignon, Kathleen R Blazer, Marinus J Blok, Carl Blomqvist, William Blot, Kristie Bobolis, Bram Boeckx, Natalia V Bogdanova, Anders Bojesen, Stig E Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Aniko Bozsik, Angela R Bradbury, Judith S Brand, Hiltrud Brauch, Hermann Brenner, Brigitte Bressac-de Paillerets, Carole Brewer, Louise Brinton, Per Broberg, Angela Brooks-Wilson, Joan Brunet, Thomas Brüning, Barbara Burwinkel, Saundra S Buys, Jinyoung Byun, Qiuyin Cai, Trinidad Caldés, Maria A Caligo, Ian Campbell, Federico Canzian, Olivier Caron, Angel Carracedo, Brian D Carter, J Esteban Castelao, Laurent Castera, Virginie Caux-Moncoutier, Salina B Chan, Jenny Chang-Claude, Stephen J Chanock, Xiaoqing Chen, Ting-Yuan David Cheng, Jocelyne Chiquette, Hans Christiansen, Kathleen B M Claes, Christine L Clarke, Thomas Conner, Don M Conroy, Jackie Cook, Emilie Cordina-Duverger, Sten Cornelissen, Isabelle Coupier, Angela Cox, David G Cox, Simon S Cross, Katarina Cuk, Julie M Cunningham, Kamila Czene, Mary B Daly, Francesca Damiola, Hatef Darabi, Rosemarie Davidson, Kim De Leeneer, Peter Devilee, Ed Dicks, Orland Diez, Yuan Chun Ding, Nina Ditsch, Kimberly F Doheny, Susan M Domchek, Cecilia M Dorfling, Thilo Dörk, Isabel dos-Santos-Silva, Stéphane Dubois, Pierre-Antoine Dugué, Martine Dumont, Alison M Dunning, Lorraine Durcan, Miriam Dwek, Bernd Dworniczak, Diana Eccles, Ros Eeles, Hans Ehrencrona, Ursula Eilber, Bent Ejlertsen, Arif B Ekici, A Heather Eliassen, Christoph Engel, Mikael Eriksson, Laura Fachal, Laurence Faivre, Peter A Fasching, Ulrike Faust, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, William D Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Pragna Gaddam, Marilie D Gammon, Patricia A Ganz, Susan M Gapstur, Judy Garber, Vanesa Garcia-Barberan, José A García-Sáenz, Mia M Gaudet, Marion Gauthier-Villars, Andrea Gehrig, Vassilios Georgoulias, Anne-Marie Gerdes, Graham G Giles, Gord Glendon, Andrew K Godwin, Mark S Goldberg, David E Goldgar, Anna González-Neira, Paul Goodfellow, Mark H Greene, Grethe I Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Daphne Gschwantler-Kaulich, Pascal Guénel, Qi Guo, Lothar Haeberle, Eric Hahnen, Christopher A Haiman, Niclas Håkansson, Emily Hallberg, Ute Hamann, Nathalie Hamel, Susan Hankinson, Thomas V O Hansen, Patricia Harrington, Steven N Hart, Jaana M Hartikainen, Catherine S Healey, Alexander Hein, Sonja Helbig, Alex Henderson, Jane Heyworth, Belynda Hicks, Peter Hillemanns, Shirley Hodgson, Frans B Hogervorst, Antoinette Hollestelle, Maartje J Hooning, Bob Hoover, John L Hopper, Chunling Hu, Guanmengqian Huang, Peter J Hulick, Keith Humphreys, David J Hunter, Evgeny N Imyanitov, Claudine Isaacs, Motoki Iwasaki, Louise Izatt, Anna Jakubowska, Paul James, Ramunas Janavicius, Wolfgang Janni, Uffe Birk Jensen, Esther M John, Nichola Johnson, Kristine Jones, Michael Jones, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Daehee Kang, Karin Kast, Renske Keeman, Michael J Kerin, Carolien M Kets, Machteld Keupers, Sofia Khan, Elza Khusnutdinova, Johanna I Kiiski, Sung-Won Kim, Julia A Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela N Kristensen, Torben A Kruse, Ava Kwong, Anne-Vibeke Lænkholm, Yael Laitman, Fiona Lalloo, Diether Lambrechts, Keren Landsman, Christine Lasset, Conxi Lazaro, Loic Le Marchand, Julie Lecarpentier, Andrew Lee, Eunjung Lee, Jong Won Lee, Min Hyuk Lee, Flavio Lejbkowicz, Fabienne Lesueur, Jingmei Li, Jenna Lilyquist, Anne Lincoln, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jennifer T Loud, Jan Lubinski, Craig Luccarini, Michael Lush, Robert J MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Kathleen E Malone, Siranoush Manoukian, JoAnn E Manson, Sara Margolin, John W M Martens, Maria Elena Martinez, Keitaro Matsuo, Dimitrios Mavroudis, Sylvie Mazoyer, Catriona McLean, Hanne Meijers-Heijboer, Primitiva Menéndez, Jeffery Meyer, Hui Miao, Austin Miller, Nicola Miller, Gillian Mitchell, Marco Montagna, Kenneth Muir, Anna Marie Mulligan, Claire Mulot, Sue Nadesan, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Dieter Niederacher, Sune F Nielsen, Børge G Nordestgaard, Aaron Norman, Robert L Nussbaum, Edith Olah, Olufunmilayo I Olopade, Janet E Olson, Curtis Olswold, Kai-ren Ong, Jan C Oosterwijk, Nick Orr, Ana Osorio, V Shane Pankratz, Laura Papi, Tjoung-Won Park-Simon, Ylva Paulsson-Karlsson, Rachel Lloyd, Inge Søkilde Pedersen, Bernard Peissel, Ana Peixoto, Jose I A Perez, Paolo Peterlongo, Julian Peto, Georg Pfeiler, Catherine M Phelan, Mila Pinchev, Dijana Plaseska-Karanfilska, Bruce Poppe, Mary E Porteous, Ross Prentice, Nadege Presneau, Darya Prokofieva, Elizabeth Pugh, Miquel Angel Pujana, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Hedy S Rennert, Valerie Rhenius, Kerstin Rhiem, Andrea Richardson, Gustavo C Rodriguez, Atocha Romero, Jane Romm, Matti A Rookus, Anja Rudolph, Thomas Ruediger, Emmanouil Saloustros, Joyce Sanders, Dale P Sandler, Suleeporn Sangrajrang, Elinor J Sawyer, Daniel F Schmidt, Minouk J Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J Scott, Sheila Seal, Leigha Senter, Caroline Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xin Sheng, Hermela Shimelis, Martha J Shrubsole, Xiao-Ou Shu, Lucy E Side, Christian F Singer, Christof Sohn, Melissa C Southey, John J Spinelli, Amanda B Spurdle, Christa Stegmaier, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Harald Surowy, Christian Sutter, Anthony Swerdlow, Csilla I Szabo, Rulla M Tamimi, Yen Y Tan, Jack A Taylor, Maria-Isabel Tejada, Maria Tengström, Soo H Teo, Mary B Terry, Daniel C Tessier, Alex Teulé, Kathrin Thöne, Darcy L Thull, Maria Grazia Tibiletti, Laima Tihomirova, Marc Tischkowitz, Amanda E Toland, Rob A E M Tollenaar, Ian Tomlinson, Ling Tong, Diana Torres, Martine Tranchant, Thérèse Truong, Kathy Tucker, Nadine Tung, Jonathan Tyrer, Hans-Ulrich Ulmer, Celine Vachon, Christi J van Asperen, David Van Den Berg, Ans M W van den Ouweland, Elizabeth J van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Alessandra Viel, Joseph Vijai, Daniel Vincent, Jason Vollenweider, Lisa Walker, Zhaoming Wang, Shan Wang-Gohrke, Barbara Wappenschmidt, Clarice R Weinberg, Jeffrey N Weitzel, Camilla Wendt, Jelle Wesseling, Alice S Whittemore, Juul T Wijnen, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H Wu, Lucy Xia, Xiaohong R Yang, Drakoulis Yannoukakos, Daniela Zaffaroni, Wei Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Kristin K Zorn, Manuela Gago-Dominguez, Arto Mannermaa, Håkan Olsson, Manuel R Teixeira, Jennifer Stone, Kenneth Offit, Laura Ottini, Sue K Park, Mads Thomassen, Per Hall, Alfons Meindl, Rita K Schmutzler, Arnaud Droit, Gary D Bader, Paul D P Pharoah, Fergus J Couch, Douglas F Easton, Peter Kraft, Georgia Chenevix-Trench, Montserrat García-Closas, Marjanka K Schmidt, Antonis C Antoniou, Jacques Simard

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.