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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

2018; Nature Portfolio; Volume: 50; Issue: 7 Linguagem: Inglês

10.1038/s41588-018-0132-x

1546-1718

Lang Wu, Wei Shi, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Jonathan Beesley, Manjeet K. Bolla, Xiao‐Ou Shu, Yingchang Lu, Qiuyin Cai, Fares Al‐Ejeh, Esdy Rozali, Qin Wang, Joe Dennis, Bingshan Li, Chenjie Zeng, Helian Feng, Alexander Gusev, Richard Barfield, Irene L. Andrulis, Hoda Anton‐Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Myrto Barrdahl, Caroline Baynes, Matthias W. Beckmann, Javier Benı́tez, Marina Bermisheva, Carl Blomqvist, Natalia Bogdanova, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Louise A. Brinton, Per Broberg, Sara Y. Brucker, Barbara Burwinkel, Trinidad Caldés, Federico Canzian, Brian D. Carter, Jose E. Castelao, Jenny Chang‐Claude, Xiaohong Chen, Ting‐Yuan David Cheng, Hans Christiansen, Christine L. Clarke, Margriet Collée, Sten Cornelissen, Fergus J. Couch, David G. Cox, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Peter Devilee, Kimberly F. Doheny, Thilo Dörk, Isabel dos‐Santos‐Silva, Martine Dumont, Miriam Dwek, Diana Eccles, Ursula Eilber, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, Laura Fachal, Peter A. Fasching, Jonine D. Figueroa, Dieter Flesch‐Janys, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago‐Dominguez, Susan M. Gapstur, Montserrat García‐Closas, Mia M. Gaudet, Maya Ghoussaini, Graham G. Giles, Mark S. Goldberg, David E. Goldgar, Anna González‐Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Emily Hallberg, Ute Hamann, Patricia Harrington, Alexander Hein, Belynda Hicks, Peter Hillemanns, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Kristine Jones, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Michael J. Kerin, Э. К. Хуснутдинова, Veli‐Matti Kosma, Vessela N. Kristensen, Diether Lambrechts, Loı̈c Le Marchand, Jingmei Li, Sara Lindström, Jolanta Lissowska, Wing‐Yee Lo, Sibylle Loibl, Jan Lubiński, Craig Luccarini, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Ivana Maleva Kostovska, Graham J. Mann, JoAnn E. Manson, Sara Margolin, Dimitrios Mavroudis, Hanne Meijers‐Heijboer, Thomas Ind, Usha Menon, Jeffery Meyer, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Sune F. Nielsen, Børge G. Nordestgaard, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Paolo Peterlongo, Julian Peto, Dijana Plaseska‐Karanfilska, Ross L. Prentice, Nadège Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Jane Romm, Anja Rudolph, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Andreas Schneeweiß, Rodney J. Scott, Christopher G. Scott, Sheila Seal, Mitul Shah, Martha J. Shrubsole, Ann Smeets, Melissa C. Southey, John J. Spinelli, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William Tapper, Jack A. Taylor, Mary Beth Terry, Daniel C. Tessier, Abigail Thomas, Kathrin Thöne, Rob A.�E.�M. Tollenaar, Diana Torres, Thérèse Truong, Michael Untch, Celine M. Vachon, David Van Den Berg, Daniel Vincent, Quinten Waisfisz, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter C. Willett, Robert Winqvist, Alicja Wolk, Lucy Xia, Xiaohong R. Yang, Argyrios Ziogas, Elad Ziv, Alison M. Dunning, Paul D.P. Pharoah, Jacques Simard, Roger L. Milne, Stacey L. Edwards, Peter Kraft, Douglas F. Easton, Georgia Chenevix‐Trench, Wei Zheng,

Bioinformatics and Genomic Networks

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10−6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology. A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.