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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
Nat Genet. 2018 Jul;50(7) :968-978
PMID: 29915430    PMCID: PMC6314198    URL: https://www.ncbi.nlm.nih.gov/pubmed/29915430
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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 < 5.82 x 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.
Notes
1546-1718 Wu, Lang Shi, Wei Long, Jirong Guo, Xingyi ORCID: http://orcid.org/0000-0001-5269-1294 Michailidou, Kyriaki Beesley, Jonathan Bolla, Manjeet K Shu, Xiao-Ou Lu, Yingchang Cai, Qiuyin Al-Ejeh, Fares ORCID: http://orcid.org/0000-0002-1553-0077 Rozali, Esdy Wang, Qin Dennis, Joe Li, Bingshan ORCID: http://orcid.org/0000-0003-2129-168X Zeng, Chenjie Feng, Helian Gusev, Alexander ORCID: http://orcid.org/0000-0002-7980-4620 Barfield, Richard T Andrulis, Irene L ORCID: http://orcid.org/0000-0002-4226-6435 Anton-Culver, Hoda Arndt, Volker ORCID: http://orcid.org/0000-0001-9320-8684 Aronson, Kristan J Auer, Paul L Barrdahl, Myrto Baynes, Caroline Beckmann, Matthias W Benitez, Javier Bermisheva, Marina Blomqvist, Carl Bogdanova, Natalia V Bojesen, Stig E Brauch, Hiltrud ORCID: http://orcid.org/0000-0001-7531-2736 Brenner, Hermann Brinton, Louise Broberg, Per Brucker, Sara Y Burwinkel, Barbara Caldes, Trinidad Canzian, Federico Carter, Brian D Castelao, J Esteban Chang-Claude, Jenny Chen, Xiaoqing Cheng, Ting-Yuan David Christiansen, Hans Clarke, Christine L NBCS Collaborators Collee, Margriet ORCID: http://orcid.org/0000-0002-9272-9346 Cornelissen, Sten Couch, Fergus J Cox, David Cox, Angela ORCID: http://orcid.org/0000-0002-5138-1099 Cross, Simon S Cunningham, Julie M ORCID: http://orcid.org/0000-0002-8159-3025 Czene, Kamila Daly, Mary B Devilee, Peter Doheny, Kimberly F Dork, Thilo Dos-Santos-Silva, Isabel Dumont, Martine Dwek, Miriam Eccles, Diana M Eilber, Ursula Eliassen, A Heather Engel, Christoph Eriksson, Mikael Fachal, Laura ORCID: http://orcid.org/0000-0002-7256-9752 Fasching, Peter A Figueroa, Jonine Flesch-Janys, Dieter Fletcher, Olivia ORCID: http://orcid.org/0000-0001-9387-7116 Flyger, Henrik Fritschi, Lin Gabrielson, Marike Gago-Dominguez, Manuela Gapstur, Susan M Garcia-Closas, Montserrat Gaudet, Mia M Ghoussaini, Maya Giles, Graham G Goldberg, Mark S Goldgar, David E Gonzalez-Neira, Anna Guenel, Pascal Hahnen, Eric Haiman, Christopher A Hakansson, Niclas Hall, Per Hallberg, Emily Hamann, Ute Harrington, Patricia Hein, Alexander ORCID: http://orcid.org/0000-0003-2601-3398 Hicks, Belynda ORCID: http://orcid.org/0000-0001-8014-4888 Hillemanns, Peter Hollestelle, Antoinette ORCID: http://orcid.org/0000-0003-1166-1966 Hoover, Robert N Hopper, John L Huang, Guanmengqian Humphreys, Keith Hunter, David J Jakubowska, Anna ORCID: http://orcid.org/0000-0002-5650-0501 Janni, Wolfgang John, Esther M Johnson, Nichola Jones, Kristine Jones, Michael E Jung, Audrey Kaaks, Rudolf Kerin, Michael J Khusnutdinova, Elza ORCID: http://orcid.org/0000-0003-2987-3334 Kosma, Veli-Matti Kristensen, Vessela N Lambrechts, Diether Le Marchand, Loic Li, Jingmei ORCID: http://orcid.org/0000-0001-8587-7511 Lindstrom, Sara Lissowska, Jolanta Lo, Wing-Yee Loibl, Sibylle Lubinski, Jan Luccarini, Craig Lux, Michael P MacInnis, Robert J Maishman, Tom Kostovska, Ivana Maleva Mannermaa, Arto Manson, JoAnn E Margolin, Sara Mavroudis, Dimitrios Meijers-Heijboer, Hanne Meindl, Alfons Menon, Usha ORCID: http://orcid.org/0000-0003-3708-1732 Meyer, Jeffery Mulligan, Anna Marie Neuhausen, Susan L Nevanlinna, Heli ORCID: http://orcid.org/0000-0002-0916-2976 Neven, Patrick Nielsen, Sune F Nordestgaard, Borge G ORCID: http://orcid.org/0000-0002-1954-7220 Olopade, Olufunmilayo I Olson, Janet E Olsson, Hakan Peterlongo, Paolo Peto, Julian Plaseska-Karanfilska, Dijana Prentice, Ross Presneau, Nadege Pylkas, Katri ORCID: http://orcid.org/0000-0002-2449-0521 Rack, Brigitte Radice, Paolo Rahman, Nazneen Rennert, Gad ORCID: http://orcid.org/0000-0002-8512-068X Rennert, Hedy S Rhenius, Valerie Romero, Atocha ORCID: http://orcid.org/0000-0002-1634-7397 Romm, Jane Rudolph, Anja Saloustros, Emmanouil ORCID: http://orcid.org/0000-0002-0485-0120 Sandler, Dale P Sawyer, Elinor J Schmidt, Marjanka K Schmutzler, Rita K Schneeweiss, Andreas Scott, Rodney J Scott, Christopher G ORCID: http://orcid.org/0000-0003-1340-0647 Seal, Sheila Shah, Mitul Shrubsole, Martha J ORCID: http://orcid.org/0000-0002-5591-7575 Smeets, Ann Southey, Melissa C Spinelli, John J Stone, Jennifer Surowy, Harald Swerdlow, Anthony J Tamimi, Rulla M Tapper, William Taylor, Jack A Terry, Mary Beth Tessier, Daniel C Thomas, Abigail Thone, Kathrin Tollenaar, Rob A E M Torres, Diana Truong, Therese Untch, Michael Vachon, Celine Van Den Berg, David Vincent, Daniel Waisfisz, Quinten Weinberg, Clarice R Wendt, Camilla Whittemore, Alice S Wildiers, Hans Willett, Walter C Winqvist, Robert Wolk, Alicja ORCID: http://orcid.org/0000-0001-7387-6845 Xia, Lucy Yang, Xiaohong R Ziogas, Argyrios ORCID: http://orcid.org/0000-0003-4529-3727 Ziv, Elad kConFab/AOCS Investigators Dunning, Alison M Pharoah, Paul D P ORCID: http://orcid.org/0000-0001-8494-732X Simard, Jacques Milne, Roger L ORCID: http://orcid.org/0000-0001-5764-7268 Edwards, Stacey L Kraft, Peter Easton, Douglas F ORCID: http://orcid.org/0000-0003-2444-3247 Chenevix-Trench, Georgia Zheng, Wei ORCID: http://orcid.org/0000-0003-1226-070X Journal Article R25 CA160056/CA/NCI NIH HHS/ P50 CA116201/CA/NCI NIH HHS/ U19 CA148065/CA/NCI NIH HHS/ R01 CA158473/CA/NCI NIH HHS/ K99 CA218892/CA/NCI NIH HHS/ Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.