Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

著者: Manuel A. R. Ferreira, Eric R. Gamazon, Fares Al‐Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton‐Culver, Aðalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmañà, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benı́tez, Marina Bermisheva, Katarzyna Białkowska, Carl Blomqvist, Natalia Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Åke Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D. Carter, Jose E. Castelao, Jenny Chang‐Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen Claes, Christine L. Clarke, EMBRACE Collaborators, Julian Adlard, Munaza Ahmed, Julian Barwell, Angela Brady, Carole Brewer, Jackie Cook, Rosemarie Davidson, Alan C. Donaldson, Jacqueline Eason, Ros Eeles, D. Gareth Evans, Helen Gregory, Helen Hanson, Alex Henderson, Shirley Hodgson, Louise Izatt, Michael J. Kennedy, Fiona Lalloo, Clare Miller, Patrick J. Morrison, Kai‐Ren Ong, Jo Perkins, Mary Porteous, Mark T. Rogers, Lucy Side, Katie Snape, Lisa Walker, Patricia A. Harrington, GC-HBOC Study Collaborators, Norbert Arnold, Bernd Auber, Nadja Bogdanova-Markov, Julika Borde, Almuth Caliebe, Nina Ditsch, Bernd Dworniczak, Stefanie Engert, Ulrike Faust, Andrea Gehrig, Eric Hahnen, Jan Hauke, Julia Hentschel, Natalie Herold, Ellen Honisch, Walter Just, Karin Kast, Mirjam Larsen, Johannes Lemke, Huu Phuc Nguyen, Dieter Niederacher, Claus‐Eric Ott, Konrad Platzer, Esther Pohl‐Rescigno, Juliane Ramser, Kerstin Rhiem, Doris Steinemann, Christian Sutter, Raymonda Varon-Mateeva, Shan Wang‐Gohrke, Bernhard H. F. Weber, GEMO Study Collaborators, Fabienne Prieur, Pascal Pujol, Charlotte Sagne, Nicolas Sévenet, Hagay Sobol, Johanna Sokolowska, Dominique Stoppa-Lyonnet, Laurence Venat-Bouvet, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Joe Dennis, Peter Devilee, Orland Dı́ez, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Domínguez, Patricia A. Ganz, Susan M. Gapstur, Judy E. Garber, Montserrat García‐Closas, José Á. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González‐Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, U. Hamann, Wei He, Jane Heyworth, Frans B. L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, ABCTB Investigators, Rosemary L. Balleine, Robert Baxter, Stephen Braye, Jane Carpenter, Jane E. Dahlstrom, John Forbes, Soon C Lee, Deborah J. Marsh, Adrienne Morey, Nirmala Pathmanathan, Peter Simpson, Allan D. Spigelman, Nicholas Wilcken, Desmond Yip, HEBON Investigators, Bernadette A. M. Heemskerk‐Gerritsen, Matti A. Rookus, Caroline Seynaeve, Frederieke H. van der Baan, Annemieke H. van der Hout, Lizet E. van der Kolk, Rob B. van der Luijt, Carolien H. M. van Deurzen, Helena C. van Doorn, Klaartje van Engelen, Liselotte van Hest, Theo A.M. van Os, Senno Verhoef, Maartje J. Vogel, Juul Wijnen, BCFR Investigators, Alexander Miron, Miroslav Kapuscinski, Anita Bane, Eric A. Ross, Saundra S. Buys, Thomas Conner, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Joseph Vijai, Beth Y. Karlan, Э. К. Хуснутдинова, Johanna I. Kiiski, Yon‐Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lázaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C. Nielsen, Liene Ņikitina-Zaķe, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osório, J. Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Søkilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D.P. Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadège Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Anthony J. Swerdlow, William Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Àlex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Thérèse Truong, Nadine Tung, Celine M. Vachon, Christi J. van Asperen, Ans M.W. van den Ouweland, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Qin Wang, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C. Antoniou, Wei Zheng, Douglas F. Easton, Roger L. Milne, Jonathan Beesley, Georgia Chenevix‐Trench - Nature Communications 2019 被引用: 138

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.