Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status

Authors: Helian Feng, Alexander Gusev, Bogdan Paşaniuc, Lang Wu, Jirong Long, Zomoroda Abu-Full, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton‐Culver, Antonis C. Antoniou, Aðalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu Arun, Ella Asseryanis, Paul L. Auer, Jacopo Azzollini, Judith Balmañà, Rósa B. Barkardóttir, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benı́tez, Marina Bermisheva, Katarzyna Białkowska, Ana Blanco, Carl Blomqvist, Bram Boeckx, Natalia Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Åke Borg, Hiltrud Brauch, Hermann Brenner, Ignacio Briceño, Annegien Broeks, Thomas Brüning, Barbara Burwinkel, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Sander Canisius, Daniele Campa, Brian D. Carter, Jonathan Carter, Jose E. Castelao, Jenny Chang‐Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, GC‐HBOC study Collaborators, Fergus J. Couch, Angela Cox, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Kim De Leeneer, Joe Dennis, Peter Devilee, Orland Dı́ez, Susan M. Domchek, Thilo Dörk, Isabel dos‐Santos‐Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, 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, Ute Hamann, Christopher R. Hake, Wei He, Jane Heyworth, Frans B.L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Guanmengqian Huang, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Joseph Vijai, Audrey Jung, Beth Y. Karlan, Э. К. Хуснутдинова, Johanna I. Kiiski, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lázaro, Dominique Leroux, Goska Leslie, Jenny Lester, Fabienne Lesueur, Noralane M. Lindor, Sara Lindström, Wing‐Yee Lo, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, John W.M. Martens, Marı́a Elena Martı́nez, Laura Matricardi, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Pooja Middha, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Taru Muranen, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn Cilius Nielsen, Liene Ņikitina-Zaķe, Kenneth Offit, Edith Oláh, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osório, J. Papp, Tjoung‐Won Park‐Simon, Michael T. Parsons, Inge Søkilde Pedersen, Ana Peixoto, Paolo Peterlongo, Julian Peto, Paul D.P. Pharoah, Kelly‐Anne Phillips, Dijana Plaseska‐Karanfilska, Bruce Poppe, Nisha Pradhan, Karolina Prajzendanc, Nadège Presneau, Kevin Punie, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Harvey A. Risch, Mark E. Robson, Atocha Romero, Emmanouil Saloustros, Dale P. Sandler, Catarina Santos, Elinor J. Sawyer, Marjanka K. Schmidt, Daniel F. Schmidt, Rita K. Schmutzler, Minouk J. Schoemaker, Rodney J. Scott, Priyanka Sharma, Xiao‐Ou Shu, Jacques Simard, Christian F. Singer, Anne‐Bine Skytte, 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, Rob A.�E.�M. Tollenaar, 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, Paula Vieiro‐Balo, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Roger L. Milne, Douglas F. Easton, Georgia Chenevix‐Trench, Wei Zheng, Peter Kraft, Xia Jiang - Genetic Epidemiology 2020 cited by 45

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.