1. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
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Harald Surowy, Rulla M. Tamimi, Javier Benitez, Wing-Yee Lo, Celine M. Vachon, Nadege Presneau, John J. Spinelli, Ann Smeets, Hoda Anton-Culver, Veli-Matti Kosma, Christopher A. Haiman, Martha J. Shrubsole, Ross L. Prentice, Diana Eccles, Ursula Eilber, Loic Le Marchand, Katri Pylkäs, Jirong Long, Michael P. Lux, Sara Margolin, Hedy S. Rennert, Tom Maishman, Mary B. Daly, Rita K. Schmutzler, Julian Peto, Sune F. Nielsen, Eric Hahnen, Niclas Håkansson, Børge G. Nordestgaard, Mitul Shah, Matthias W. Beckmann, Anthony J. Swerdlow, Barbara Burwinkel, Rudolf Kaaks, Usha Menon, William J. Tapper, Argyrios Ziogas, Peter Hillemanns, Fares Al-Ejeh, Roger L. Milne, Wolfgang Janni, Pascal Guénel, Mikael Eriksson, Clarice R. Weinberg, Kyriaki Michailidou, Jonathan Beesley, Marike Gabrielson, J. Esteban Castelao, Margriet Collée, Janet E. Olson, Gad Rennert, Per Broberg, Rob A. E. M. Tollenaar, David Cox, Paolo Peterlongo, Helian Feng, Brian D. Carter, Nichola Johnson, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Kimberly F. Doheny, Paul L. Auer, Hans Wildiers, Jacques Simard, Michael Untch, Per Hall, Martine Dumont, Julie M. Cunningham, Thilo Dörk, Mary Beth Terry, Jenny Chang-Claude, Lang Wu, Irene L. Andrulis, Xiaohong R. Yang, Caroline Baynes, Isabel dos-Santos-Silva, Douglas F. Easton, Wei Shi, Emily Hallberg, Camilla Wendt, Hiltrud Brauch, Diana Torres, Olufunmilayo I. Olopade, David Van Den Berg, Georgia Chenevix-Trench, Alfons Meindl, Stig E. Bojesen, Jonine D. Figueroa, Dale P. Sandler, Vessela N. Kristensen, Christine L. Clarke, Wei Zheng, Manuela Gago-Dominguez, E Rozali, Henrik Flyger, Sheila Seal, Guanmengqian Huang, Marjanka K. Schmidt, Håkan Olsson, Christopher G. Scott, Kamila Czene, Laura Fachal, Rodney J. Scott, Jennifer Stone, Sara Y. Brucker, Qin Wang, David J. Hunter, Maya Ghoussaini, Christoph Engel, Keith Humphreys, Susan M. Gapstur, Daniel C. Tessier, Paolo Radice, John L. Hopper, Audrey Y. Jung, Lucy Xia, Atocha Romero, Chenjie Zeng, Peter A. Fasching, Jan Lubinski, Anna González-Neira, Nazneen Rahman, Robert N. Hoover, Thérèse Truong, Fergus J. Couch, Anna Marie Mulligan, Robert J. MacInnis, Ute Hamann, Hanne Meijers-Heijboer, Brigitte Rack, Simon S. Cross, Federico Canzian, J.-P. Meyer, Sara Lindström, Natalia Bogdanova, Trinidad Caldés, Olivia Fletcher, Peter Kraft, Elinor J. Sawyer, Alexander Gusev, Louise A. Brinton, Diether Lambrechts, Bingshan Li, Kristan J. Aronson, Jane Romm, Anja Rudolph, Peter Devilee, Qiuyin Cai, Arto Mannermaa, Elad Ziv, Alice S. Whittemore, Abigail Thomas, Hermann Brenner, Montserrat Garcia-Closas, Patrick Neven, Kristine Jones, Miriam Dwek, Sibylle Loibl, Heli Nevanlinna, Jolanta Lissowska, Susan L. Neuhausen, Elza Khusnutdinova, Marina Bermisheva, Alicja Wolk, Lin Fritschi, Xingyi Guo, Angela Cox, Michael Jones, Xiaoqing Chen, Esther M. John, Richard Barfield, Volker Arndt, Patricia Harrington, Quinten Waisfisz, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Stacey L. Edwards, Melissa C. Southey, Andreas Schneeweiss, Jack A. Taylor, Robert Winqvist, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Kathrin Thöne, Dieter Flesch-Janys, Mark S. Goldberg, Craig Luccarini, Sten Cornelissen, Jingmei Li, Michael J. Kerin, Myrto Barrdahl, Xiao-Ou Shu, Alison M. Dunning, Manjeet K. Bolla, Carl Blomqvist, Graham G. Giles, Hans Christiansen, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Belynda Hicks, Ivana Maleva Kostovska, Tongguang Cheng, Yingchang Lu, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Medical Oncology, Guo, Xingyi [0000-0001-5269-1294], Al-Ejeh, Fares [0000-0002-1553-0077], Li, Bingshan [0000-0003-2129-168X], Gusev, Alexander [0000-0002-7980-4620], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Collée, Margriet [0000-0002-9272-9346], Cox, Angela [0000-0002-5138-1099], Cunningham, Julie M [0000-0002-8159-3025], Fachal, Laura [0000-0002-7256-9752], Fletcher, Olivia [0000-0001-9387-7116], Hein, Alexander [0000-0003-2601-3398], Hicks, Belynda [0000-0001-8014-4888], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Khusnutdinova, Elza [0000-0003-2987-3334], Li, Jingmei [0000-0001-8587-7511], Menon, Usha [0000-0003-3708-1732], Nevanlinna, Heli [0000-0002-0916-2976], Nordestgaard, Børge G [0000-0002-1954-7220], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher G [0000-0003-1340-0647], Shrubsole, Martha J [0000-0002-5591-7575], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul DP [0000-0001-8494-732X], Milne, Roger L [0000-0001-5764-7268], Easton, Douglas F [0000-0003-2444-3247], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Human Genetics, and ARD - Amsterdam Reproduction and Development
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0301 basic medicine ,Risk ,medicine.medical_specialty ,Gene Expression ,Genome-wide association study ,Breast Neoplasms ,Biology ,Genome-wide association studies ,Polymorphism, Single Nucleotide ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,SDG 3 - Good Health and Well-being ,Genetic model ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic association ,medicine.disease ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,Case-Control Studies ,Expression quantitative trait loci ,Medical genetics ,Female ,Gene expression ,Breast Cancer Genetics ,Genome-Wide Association Study - Abstract
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 −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.
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- 2019