Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Manuel A Ferreira, Eric R Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J Aronson, Banu K Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R Barnes, Daniel Barrowdale, Matthias W Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna BiałkowskaCarl Blomqvist, Natalia V Bogdanova, Stig E Bojesen, Manjeet K Bolla, Ake Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D Carter, Jose E Castelao, Jenny Chang-Claude, Stephen J Chanock, Hans Christiansen, Wendy K Chung, Kathleen B M Claes, Christine L Clarke, GC-HBOC Study Collaborators, GEMO Study Collaborators, EMBRACE Collaborators, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Mary B Daly, Miguel de la Hoya, Joe Dennis, Peter Devilee, Orland Diez, Thilo Dörk, Alison M Dunning, Miriam Dwek, Diana M Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Patricia A Ganz, Susan M Gapstur, Judy Garber, Montserrat García-Closas, José A. 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, Wei He, Jane Heyworth, Frans B L Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L Hopper, Peter J Hulick, Keith Humphreys, Evgeny N Imyanitov, HEBON Investigators, BCFR Investigators, ABCTB Investigators, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M John, Nichola Johnson, Vijai Joseph, Beth Y Karlan, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C Nielsen, Liene Nikitina-Zake, Robert L Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I Olopade, Håkan Olsson, Ana Osorio, Janos Papp, Tjoung-Won Park-Simon, Michael T Parsons, Inge Sokilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D P Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadege Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J Sawyer, Marjanka K Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F Singer, Penny Soucy, Melissa C Southey, John J Spinelli, Amanda B Spurdle, Jennifer Stone, Anthony J. Swerdlow, William J. Tapper, Jack A. Taylor, Manuel R Teixeira, Mary Beth Terry, Alex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L Thull, Marc Tischkowitz, Amanda E. Toland, 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, Qin Wang, Barbara Wappenschmidt, Jeffrey N Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C Antoniou, Wei Zheng, Douglas F Easton, Roger L Milne, Jonathan Beesley, Georgia Chenevix-Trench

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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.

OriginalsprogEngelsk
Artikelnummer1741
TidsskriftNature Communications
Vol/bind10
Udgave nummer1
ISSN2041-1723
DOI
StatusUdgivet - 15 apr. 2019

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