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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
Nat Commun. 2019 Apr 15;10(1) :1741
PMID: 30988301    PMCID: PMC6465407   
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Abstract
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.
Notes
2041-1723 Ferreira, Manuel A Gamazon, Eric R Orcid: 0000-0003-4204-8734 Al-Ejeh, Fares Aittomaki, Kristiina Andrulis, Irene L Orcid: 0000-0002-4226-6435 Anton-Culver, Hoda Arason, Adalgeir Orcid: 0000-0003-0480-886x Arndt, Volker Orcid: 0000-0001-9320-8684 Aronson, Kristan J Arun, Banu K Asseryanis, Ella Azzollini, Jacopo Balmana, Judith Barnes, Daniel R Orcid: 0000-0002-3781-7570 Barrowdale, Daniel Beckmann, Matthias W Behrens, Sabine Benitez, Javier Bermisheva, Marina Bialkowska, Katarzyna Blomqvist, Carl Bogdanova, Natalia V Bojesen, Stig E Orcid: 0000-0002-4061-4133 Bolla, Manjeet K Borg, Ake Brauch, Hiltrud Brenner, Hermann Broeks, Annegien Burwinkel, Barbara Caldes, Trinidad Caligo, Maria A Campa, Daniele Campbell, Ian Orcid: 0000-0002-7773-4155 Canzian, Federico Carter, Jonathan Carter, Brian D Castelao, Jose E Chang-Claude, Jenny Chanock, Stephen J Orcid: 0000-0002-2324-3393 Christiansen, Hans Chung, Wendy K Claes, Kathleen B M Orcid: 0000-0003-0841-7372 Clarke, Christine L EMBRACE Collaborators GC-HBOC Study Collaborators GEMO Study Collaborators Couch, Fergus J Cox, Angela Cross, Simon S Czene, Kamila Daly, Mary B de la Hoya, Miguel Dennis, Joe Orcid: 0000-0003-4591-1214 Devilee, Peter Orcid: 0000-0002-8023-2009 Diez, Orland Dork, Thilo Dunning, Alison M Dwek, Miriam Eccles, Diana M Ejlertsen, Bent Ellberg, Carolina Orcid: 0000-0001-7297-0645 Engel, Christoph Eriksson, Mikael Fasching, Peter A Orcid: 0000-0003-4885-8471 Fletcher, Olivia Orcid: 0000-0001-9387-7116 Flyger, Henrik Friedman, Eitan Frost, Debra Gabrielson, Marike Gago-Dominguez, Manuela Ganz, Patricia A Gapstur, Susan M Garber, Judy Garcia-Closas, Montserrat Garcia-Saenz, Jose A Orcid: 0000-0001-6880-0301 Gaudet, Mia M Giles, Graham G Glendon, Gord Godwin, Andrew K Goldberg, Mark S Goldgar, David E Gonzalez-Neira, Anna Greene, Mark H Orcid: 0000-0003-1852-9239 Gronwald, Jacek Guenel, Pascal Orcid: 0000-0002-8359-518x Haiman, Christopher A Hall, Per Hamann, Ute He, Wei Heyworth, Jane Hogervorst, Frans B L Hollestelle, Antoinette Orcid: 0000-0003-1166-1966 Hoover, Robert N Hopper, John L Hulick, Peter J Orcid: 0000-0001-8397-4078 Humphreys, Keith Imyanitov, Evgeny N ABCTB Investigators HEBON Investigators BCFR Investigators Isaacs, Claudine Jakimovska, Milena Orcid: 0000-0002-1506-0669 Jakubowska, Anna James, Paul A Orcid: 0000-0002-4361-4657 Janavicius, Ramunas Jankowitz, Rachel C John, Esther M Johnson, Nichola Joseph, Vijai Orcid: 0000-0002-7933-151x Karlan, Beth Y Khusnutdinova, Elza Kiiski, Johanna I Ko, Yon-Dschun Jones, Michael E Konstantopoulou, Irene Kristensen, Vessela N Laitman, Yael Lambrechts, Diether Orcid: 0000-0002-3429-302x Lazaro, Conxi Leslie, Goska Orcid: 0000-0001-5756-6222 Lester, Jenny Lesueur, Fabienne Lindstrom, Sara Long, Jirong Loud, Jennifer T Lubinski, Jan Makalic, Enes Mannermaa, Arto Manoochehri, Mehdi Margolin, Sara Maurer, Tabea Mavroudis, Dimitrios McGuffog, Lesley Meindl, Alfons Menon, Usha Orcid: 0000-0003-3708-1732 Michailidou, Kyriaki Orcid: 0000-0001-7065-1237 Miller, Austin Orcid: 0000-0001-9739-8462 Montagna, Marco Moreno, Fernando Moserle, Lidia Mulligan, Anna Marie Nathanson, Katherine L Orcid: 0000-0002-6740-0901 Neuhausen, Susan L Nevanlinna, Heli Orcid: 0000-0002-0916-2976 Nevelsteen, Ines Nielsen, Finn C Nikitina-Zake, Liene Orcid: 0000-0003-2491-5187 Nussbaum, Robert L Offit, Kenneth Olah, Edith Olopade, Olufunmilayo I Orcid: 0000-0002-9936-1599 Olsson, Hakan Osorio, Ana Papp, Janos Park-Simon, Tjoung-Won Parsons, Michael T Orcid: 0000-0003-3242-8477 Pedersen, Inge Sokilde Orcid: 0000-0002-9902-8040 Peixoto, Ana Peterlongo, Paolo Pharoah, Paul D P Orcid: 0000-0001-8494-732x Plaseska-Karanfilska, Dijana Poppe, Bruce Presneau, Nadege Radice, Paolo Rantala, Johanna Rennert, Gad Orcid: 0000-0002-8512-068x Risch, Harvey A Saloustros, Emmanouil Orcid: 0000-0002-0485-0120 Sanden, Kristin Sawyer, Elinor J Schmidt, Marjanka K Orcid: 0000-0002-2228-429x Schmutzler, Rita K Sharma, Priyanka Shu, Xiao-Ou Simard, Jacques Singer, Christian F Soucy, Penny Southey, Melissa C Spinelli, John J Orcid: 0000-0002-9119-3287 Spurdle, Amanda B Stone, Jennifer Orcid: 0000-0001-5077-0124 Swerdlow, Anthony J Tapper, William J Taylor, Jack A Teixeira, Manuel R Orcid: 0000-0002-4896-5982 Terry, Mary Beth Teule, Alex Thomassen, Mads Thone, Kathrin Thull, Darcy L Tischkowitz, Marc Toland, Amanda E Orcid: 0000-0002-0271-1792 Torres, Diana Truong, Therese Orcid: 0000-0002-2943-6786 Tung, Nadine Vachon, Celine M van Asperen, Christi J van den Ouweland, Ans M W van Rensburg, Elizabeth J Vega, Ana Viel, Alessandra Orcid: 0000-0003-2804-0840 Wang, Qin Wappenschmidt, Barbara Weitzel, Jeffrey N Wendt, Camilla Winqvist, Robert Yang, Xiaohong R Yannoukakos, Drakoulis Ziogas, Argyrios Orcid: 0000-0003-4529-3727 Kraft, Peter Antoniou, Antonis C Zheng, Wei Easton, Douglas F Orcid: 0000-0003-2444-3247 Milne, Roger L Beesley, Jonathan Orcid: 0000-0001-5764-7268 Chenevix-Trench, Georgia Journal Article England Nat Commun. 2019 Apr 15;10(1):1741. doi: 10.1038/s41467-018-08053-5.