Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
Manuel A. R. Ferreira(QIMR Berghofer Medical Research Institute), Eric R. Gamazon(Vanderbilt University), Fares Al‐Ejeh(QIMR Berghofer Medical Research Institute), Kristiina Aittomäki(University of Helsinki), Irene L. Andrulis(Mount Sinai Hospital), Hoda Anton‐Culver(University of California, Irvine), Aðalgeir Arason(Reykjavík University), Volker Arndt(German Cancer Research Center), Kristan J. Aronson(Queen's University), Banu Arun(The University of Texas MD Anderson Cancer Center), Ella Asseryanis(Comprehensive Cancer Center Vienna), Jacopo Azzollini(Fondazione IRCCS Istituto Nazionale dei Tumori), Judith Balmañà(Hebron University), Daniel R. Barnes(University of Cambridge), Daniel Barrowdale(University of Cambridge), Matthias W. Beckmann(Universitätsklinikum Erlangen), Sabine Behrens(German Cancer Research Center), Javier Benı́tez(Spanish National Cancer Research Centre), Marina Bermisheva(Ufa Institute of Chemistry), Katarzyna Białkowska(Pomeranian Medical University), Carl Blomqvist(University of Helsinki), Natalia Bogdanova(Medizinische Hochschule Hannover), Stig E. Bojesen(University of Copenhagen), Manjeet K. Bolla(University of Cambridge), Åke Borg(Lund University), Hiltrud Brauch(German Cancer Research Center), Hermann Brenner(German Cancer Research Center), Annegien Broeks(The Netherlands Cancer Institute), Barbara Burwinkel(German Cancer Research Center), Trinidad Caldés(Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Maria A. Caligo(Azienda Ospedaliera Universitaria Pisana), Daniele Campa(University of Pisa), Ian Campbell(The University of Melbourne), Federico Canzian(German Cancer Research Center), Jonathan Carter(The University of Sydney), Brian D. Carter(American Cancer Society), Jose E. Castelao(Servicio Gallego de Salud), Jenny Chang‐Claude(Universität Hamburg), Stephen J. Chanock(National Institutes of Health), Hans Christiansen(Medizinische Hochschule Hannover), Wendy K. Chung(Columbia University), Kathleen Claes(Ghent University), Christine L. Clarke(The University of Sydney), EMBRACE Collaborators(Chapel Allerton Hospital), Julian Adlard(Great Ormond Street Hospital), Munaza Ahmed(University Hospitals of Leicester NHS Trust), Julian Barwell(London North West Healthcare NHS Trust), Angela Brady(Royal Devon and Exeter Hospital), Carole Brewer(Sheffield Children's Hospital), Jackie Cook(University of Glasgow), Rosemarie Davidson(St Michael's Hospital), Alan C. Donaldson(Nottingham University Hospitals NHS Trust), Jacqueline Eason(Royal Marsden NHS Foundation Trust), Ros Eeles(Manchester Academic Health Science Centre), D. Gareth Evans(University of Aberdeen), Helen Gregory(St George's Hospital), Helen Hanson(Centre for Life), Alex Henderson(St George's, University of London), Shirley Hodgson(Guy's and St Thomas' NHS Foundation Trust), Louise Izatt(Trinity College Dublin), Michael J. Kennedy(Manchester Academic Health Science Centre), Fiona Lalloo(University of Liverpool), Clare Miller(University of Ulster), Patrick J. Morrison(Birmingham Women's Hospital), Kai‐Ren Ong(University of Cambridge), Jo Perkins(Western General Hospital), Mary Porteous(University Hospital of Wales), Mark T. Rogers(Princess Anne Hospital), Lucy Side(St George's, University of London), Katie Snape(Churchill Hospital), Lisa Walker(University of Cambridge), Patricia A. Harrington(Christian-Albrechts-Universität zu Kiel), GC-HBOC Study Collaborators(Medizinische Hochschule Hannover), Norbert Arnold(University of Münster), Bernd Auber(University of Cologne), Nadja Bogdanova-Markov(Christian-Albrechts-Universität zu Kiel), Julika Borde(Ludwig-Maximilians-Universität München), Almuth Caliebe(University of Münster), Nina Ditsch(TUM Klinikum), Bernd Dworniczak(University of Tübingen), Stefanie Engert(University of Würzburg), Ulrike Faust(University of Cologne), Andrea Gehrig(University of Cologne), Eric Hahnen(University Hospital Leipzig), Jan Hauke(University of Cologne), Julia Hentschel(Düsseldorf University Hospital), Natalie Herold(University Hospital Ulm), Ellen Honisch(Technische Universität Dresden), Walter Just(University of Cologne), Karin Kast(University Hospital Leipzig), Mirjam Larsen(University of Tübingen), Johannes Lemke(Düsseldorf University Hospital), Huu Phuc Nguyen(Charité - Universitätsmedizin Berlin), Dieter Niederacher(University Hospital Leipzig), Claus‐Eric Ott(University of Cologne), Konrad Platzer(TUM Klinikum), Esther Pohl‐Rescigno(University of Cologne), Juliane Ramser(Medizinische Hochschule Hannover), Kerstin Rhiem(Heidelberg University), Doris Steinemann(Charité - Universitätsmedizin Berlin), Christian Sutter(University Hospital Ulm), Raymonda Varon-Mateeva(University of Regensburg), Shan Wang‐Gohrke(Hôpital Nord), Bernhard H. F. Weber(Hôpital Arnaud de Villeneuve), GEMO Study Collaborators(Centre Léon Bérard), Fabienne Prieur(Institut Bergonié), Pascal Pujol(Aix-Marseille Université), Charlotte Sagne(Centre Hospitalier Régional et Universitaire de Nancy), Nicolas Sévenet(Délégation Paris 5), Hagay Sobol(Hôpital Dupuytren), Johanna Sokolowska(Mayo Clinic in Arizona), Dominique Stoppa-Lyonnet(University of Sheffield), Laurence Venat-Bouvet(University of Sheffield), Fergus J. Couch(Karolinska Institutet), Angela Cox(Fox Chase Cancer Center), Simon S. Cross(Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Kamila Czene(University of Cambridge), Mary B. Daly(Fox Chase Cancer Center), Miguel de la Hoya(Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Joe Dennis(University of Cambridge), Peter Devilee(University of Cambridge), Orland Dı́ez(Vall d'Hebron Institute of Oncology), Thilo Dörk(Medizinische Hochschule Hannover), Alison M. Dunning(University of Cambridge), Miriam Dwek(Lund University), Diana M. Eccles(University of Southampton), Bent Ejlertsen(Copenhagen University Hospital), Carolina Ellberg(University of California, Los Angeles), Christoph Engel(Institute of Cancer Research), Mikael Eriksson(Copenhagen University Hospital), Peter A. Fasching(University of California, Los Angeles), Olivia Fletcher(Institute of Cancer Research), Henrik Flyger(Copenhagen University Hospital), Eitan Friedman(Tel Aviv University), Debra Frost(University of Cambridge), Marike Gabrielson(American Cancer Society), Manuela Gago-Domínguez(University of California San Diego), Patricia A. Ganz(Institute of Cancer Research), Susan M. Gapstur(American Cancer Society), Judy E. Garber(American Cancer Society), Montserrat García‐Closas(National Institutes of Health), José Á. García-Sáenz(Mount Sinai Hospital), Mia M. Gaudet(American Cancer Society), Graham G. Giles(The University of Melbourne), Gord Glendon(Mount Sinai Hospital), Andrew K. Godwin(University Medical Center), Mark S. Goldberg(Royal Victoria Hospital), David E. Goldgar(University of Utah), Anna González‐Neira(Inserm), Mark H. Greene(University of Southern California), Jacek Gronwald(Stockholm South General Hospital), Pascal Guénel(Inserm), Christopher A. Haiman(University of Southern California), Per Hall(The University of Western Australia), U. Hamann(German Cancer Research Center), Wei He(Karolinska Institutet), Jane Heyworth(National Institutes of Health), Frans B. L. Hogervorst(The University of Melbourne), Antoinette Hollestelle(NorthShore University HealthSystem), Robert N. Hoover(National Institutes of Health), John L. Hopper(The University of Melbourne), Peter J. Hulick(NorthShore University HealthSystem), Keith Humphreys(The University of Sydney), Evgeny N. Imyanitov(John Hunter Hospital), ABCTB Investigators(The University of Sydney), Rosemary L. Balleine(Australian National University), Robert Baxter(Breast Cancer Trials), Stephen Braye(Western Sydney University), Jane Carpenter(The University of Sydney), Jane E. Dahlstrom(St Vincent's Hospital Sydney), John Forbes(Westmead Hospital), Soon C Lee(The University of Queensland), Deborah J. Marsh(St Vincent's Hospital Melbourne), Adrienne Morey(Westmead Hospital), Nirmala Pathmanathan(Canberra Hospital), Peter Simpson(Erasmus MC Cancer Institute), Allan D. Spigelman(The Netherlands Cancer Institute), Nicholas Wilcken(Erasmus MC Cancer Institute), Desmond Yip(The Netherlands Cancer Institute), HEBON Investigators(University Medical Center Groningen), Bernadette A. M. Heemskerk‐Gerritsen(The Netherlands Cancer Institute), Matti A. Rookus(University Medical Center Utrecht), Caroline Seynaeve(Erasmus MC), Frederieke H. van der Baan(Erasmus MC Cancer Institute), Annemieke H. van der Hout(University Medical Center), Lizet E. van der Kolk(Amsterdam University Medical Centers), Rob B. van der Luijt(Amsterdam University Medical Centers), Carolien H. M. van Deurzen(The Netherlands Cancer Institute), Helena C. van Doorn(The Netherlands Cancer Institute), Klaartje van Engelen(Leiden University Medical Center), Liselotte van Hest(Harvard University), Theo A.M. van Os(The University of Melbourne), Senno Verhoef(Juravinski Hospital), Maartje J. Vogel(Fox Chase Cancer Center), Juul Wijnen(Huntsman Cancer Institute), BCFR Investigators(Huntsman Cancer Institute), Alexander Miron(Georgetown University), Miroslav Kapuscinski(Macedonian Academy of Sciences and Arts), Anita Bane(Pomeranian Medical University), Eric A. Ross(Peter MacCallum Cancer Centre), Saundra S. Buys(Vilnius University), Thomas Conner(UPMC Hillman Cancer Center), Claudine Isaacs(Georgetown University), Milena Jakimovska(Institute of Cancer Research), Anna Jakubowska(Memorial Sloan Kettering Cancer Center), Paul A. James(University of California, Los Angeles), Ramunas Janavicius(Vilnius University), Rachel C. Jankowitz(University of Helsinki), Esther M. John(Johanniter-Krankenhaus Bonn), Nichola Johnson(Institute of Cancer Research), Joseph Vijai(Memorial Sloan Kettering Cancer Center), Beth Y. Karlan(Oslo University Hospital), Э. К. Хуснутдинова(Sheba Medical Center), Johanna I. Kiiski(University of Helsinki), Yon‐Dschun Ko(Institut d'Investigació Biomédica de Bellvitge), Michael E. Jones(Institute of Cancer Research), Irene Konstantopoulou(University of California, Los Angeles), Vessela N. Kristensen(Oslo University Hospital), Yael Laitman(University of Washington), Diether Lambrechts(Vanderbilt University), Conxi Lázaro(Institut d'Investigació Biomédica de Bellvitge), Goska Leslie(University of Cambridge), Jenny Lester(University of California, Los Angeles), Fabienne Lesueur(Inserm), Sara Lindström(German Cancer Research Center), Jirong Long(Vanderbilt University), Jennifer T. Loud(Universität Hamburg), Jan Lubiński(University Hospital of Heraklion), Enes Makalic(The University of Melbourne), Arto Mannermaa(University of Eastern Finland), Mehdi Manoochehri(German Cancer Research Center), Sara Margolin(Karolinska Institutet), Tabea Maurer(Roswell Park Comprehensive Cancer Center), Dimitrios Mavroudis(Istituto Oncologico Veneto), Lesley McGuffog(University of Cambridge), Alfons Meindl(Istituto Oncologico Veneto), Usha Menon(University Health Network), Kyriaki Michailidou(University of Cambridge), Austin Miller(Roswell Park Comprehensive Cancer Center), Marco Montagna(University of Helsinki), Fernando Moreno(Hospital Clínico San Carlos), Lidia Moserle(Copenhagen University Hospital), Anna Marie Mulligan(University Health Network), Katherine L. Nathanson(University of California, San Francisco), Susan L. Neuhausen(Memorial Sloan Kettering Cancer Center), Heli Nevanlinna(University of Helsinki), Ines Nevelsteen(University of Chicago), Finn C. Nielsen(Lund University), Liene Ņikitina-Zaķe(Latvian Biomedical Research and Study Centre), Robert L. Nussbaum(University of California, San Francisco), Kenneth Offit(Memorial Sloan Kettering Cancer Center), Edith Olah(QIMR Berghofer Medical Research Institute), Olufunmilayo I. Olopade(Aalborg University Hospital), Håkan Olsson(Lund University), Ana Osório(Spanish National Cancer Research Centre), J. Papp(University of Cambridge), Tjoung-Won Park-Simon(Macedonian Academy of Sciences and Arts), Michael T. Parsons(QIMR Berghofer Medical Research Institute), Inge Søkilde Pedersen(Aalborg University Hospital), Ana Peixoto(Instituto Português de Oncologia Francisco Gentil), Paolo Peterlongo(Karolinska Institutet), Paul D.P. Pharoah(University of Cambridge), Dijana Plaseska-Karanfilska(Macedonian Academy of Sciences and Arts), Bruce Poppe(Ghent University), Nadège Presneau(City of Hope), Paolo Radice(Guy's Hospital), Johanna Rantala(Karolinska Institutet), Gad Rennert(University of Cologne), Harvey A. Risch(Yale University), Emmanouil Saloustros(Vanderbilt University), Kristin Sanden(Centre hospitalier universitaire de Québec), Elinor J. Sawyer(Guy's Hospital), Marjanka K. Schmidt(The Netherlands Cancer Institute), Rita K. Schmutzler(The University of Melbourne), Priyanka Sharma(University of British Columbia), Xiao-Ou Shu(Vanderbilt University), Jacques Simard(The University of Western Australia), Christian F. Singer(Institute of Cancer Research), Penny Soucy(Centre hospitalier universitaire de Québec), Melissa C. Southey(The University of Melbourne), John J. Spinelli(University of British Columbia), Amanda B. Spurdle(QIMR Berghofer Medical Research Institute), Jennifer Stone(The University of Melbourne), Anthony J. Swerdlow(Institute of Cancer Research), William Tapper(Universität Hamburg), Jack A. Taylor(University of Pittsburgh), Manuel R. Teixeira(Universidade do Porto), Mary Beth Terry(The Ohio State University), Àlex Teulé(Pontificia Universidad Javeriana), Mads Thomassen(Inserm), Kathrin Thöne(Beth Israel Deaconess Medical Center), Darcy L. Thull(University of Pittsburgh), Marc Tischkowitz(University of Cambridge), Amanda E. Toland(Erasmus MC), Diana Torres(German Cancer Research Center), Thérèse Truong(Inserm), Nadine Tung(Beth Israel Deaconess Medical Center), Celine M. Vachon(University of Cambridge), Christi J. van Asperen(University of Cologne), Ans M.W. van den Ouweland(Erasmus MC), Elizabeth J. van Rensburg(Karolinska Institutet), Ana Vega(Fundación Pública Galega de Medicina Xenómica), Alessandra Viel(National Institutes of Health), Qin Wang(National Centre of Scientific Research "Demokritos"), Barbara Wappenschmidt(University of Cologne), Jeffrey N. Weitzel(Harvard University), Camilla Wendt(University of Cambridge), Robert Winqvist(Vanderbilt University), Xiaohong R. Yang(National Institutes of Health), Drakoulis Yannoukakos(The University of Melbourne), Argyrios Ziogas(University of California, Irvine), Peter Kraft(Harvard University), Antonis C. Antoniou(University of Cambridge), Wei Zheng(Vanderbilt University), Douglas F. Easton(University of Cambridge), Roger L. Milne(The University of Melbourne), Jonathan Beesley(QIMR Berghofer Medical Research Institute), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute)
Cited by 138Open Access
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.
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