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 Białkowska, Carl 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, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel 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, 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 A. 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. Asperen, Ans M. W. Ouweland, Elizabeth J. 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 and Georgia Chenevix-Trench
Additional contact information
Manuel A. 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: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Hoda Anton-Culver: University of California Irvine
Adalgeir Arason: Landspitali University Hospital
Volker Arndt: German Cancer Research Center (DKFZ)
Kristan J. Aronson: Queen’s University
Banu K. Arun: University of Texas MD Anderson Cancer Center
Ella Asseryanis: Medical University of Vienna
Jacopo Azzollini: Fondazione IRCCS Istituto Nazionale dei Tumori (INT)
Judith Balmaña: Vall dHebron Institute of Oncology (VHIO)
Daniel R. Barnes: University of Cambridge
Daniel Barrowdale: University of Cambridge
Matthias W. Beckmann: Friedrich-Alexander-University Erlangen-Nuremberg
Sabine Behrens: German Cancer Research Center (DKFZ)
Javier Benitez: Centro de Investigación en Red de Enfermedades Raras (CIBERER)
Marina Bermisheva: Ufa Federal Research Centre of Russian Academy of Sciences
Katarzyna Białkowska: Pomeranian Medical University
Carl Blomqvist: University of Helsinki
Natalia V. Bogdanova: Hannover Medical School
Stig E. Bojesen: Herlev and Gentofte Hospital, Copenhagen University Hospital
Manjeet K. Bolla: University of Cambridge
Ake Borg: Lund University and Skåne University Hospital
Hiltrud Brauch: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Hermann Brenner: German Cancer Research Center (DKFZ)
Annegien Broeks: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Barbara Burwinkel: German Cancer Research Center (DKFZ)
Trinidad Caldés: IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Maria A. Caligo: University Hospital of Pisa
Daniele Campa: German Cancer Research Center (DKFZ)
Ian Campbell: Peter MacCallum Cancer Center
Federico Canzian: German Cancer Research Center (DKFZ)
Jonathan Carter: Chris O’Brien Lifehouse and The University of Sydney
Brian D. Carter: American Cancer Society
Jose E. Castelao: Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Stephen J. Chanock: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
Hans Christiansen: Hannover Medical School
Wendy K. Chung: Columbia University
Kathleen B. M. Claes: Ghent University
Christine L. Clarke: University of Sydney
Fergus J. Couch: Mayo Clinic
Angela Cox: University of Sheffield
Simon S. Cross: University of Sheffield
Kamila Czene: Karolinska Institutet
Mary B. Daly: Fox Chase Cancer Center
Miguel Hoya: IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Joe Dennis: University of Cambridge
Peter Devilee: Leiden University Medical Center
Orland Diez: Vall dHebron Institute of Oncology (VHIO)
Thilo Dörk: Hannover Medical School
Alison M. Dunning: University of Cambridge
Miriam Dwek: University of Westminster
Diana M. Eccles: University of Southampton
Bent Ejlertsen: Copenhagen University Hospital
Carolina Ellberg: Lund University
Mikael Eriksson: Karolinska Institutet
Peter A. Fasching: Friedrich-Alexander-University Erlangen-Nuremberg
Olivia Fletcher: The Institute of Cancer Research
Henrik Flyger: Copenhagen University Hospital
Eitan Friedman: Chaim Sheba Medical Center
Debra Frost: University of Cambridge
Marike Gabrielson: Karolinska Institutet
Manuela Gago-Dominguez: Complejo Hospitalario Universitario de Santiago, SERGAS
Patricia A. Ganz: Jonsson Comprehensive Cancer Centre, UCLA
Susan M. Gapstur: American Cancer Society
Judy Garber: Dana-Farber Cancer Institute
Montserrat García-Closas: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
José A. García-Sáenz: Centro Investigación Biomédica en Red de Cáncer (CIBERONC)
Mia M. Gaudet: American Cancer Society
Graham G. Giles: Cancer Council Victoria
Gord Glendon: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Andrew K. Godwin: Kansas University Medical Center
Mark S. Goldberg: McGill University
David E. Goldgar: University of Utah School of Medicine
Anna González-Neira: Spanish National Cancer Research Centre (CNIO)
Mark H. Greene: National Cancer Institute
Jacek Gronwald: Pomeranian Medical University
Pascal Guénel: University Paris-Saclay
Christopher A. Haiman: University of Southern California
Per Hall: Karolinska Institutet
Ute Hamann: German Cancer Research Center (DKFZ)
Wei He: Karolinska Institutet
Jane Heyworth: The University of Western Australia
Frans B. L. Hogervorst: The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital
Antoinette Hollestelle: Erasmus MC Cancer Institute
Robert N. Hoover: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
John L. Hopper: The University of Melbourne
Peter J. Hulick: NorthShore University HealthSystem
Keith Humphreys: Karolinska Institutet
Evgeny N. Imyanitov: N.N. Petrov Institute of Oncology. St.
Claudine Isaacs: Georgetown University
Milena Jakimovska: Macedonian Academy of Sciences and Arts
Anna Jakubowska: Pomeranian Medical University
Paul A. James: The University of Melbourne
Ramunas Janavicius: Vilnius University Hospital Santariskiu Clinics
Rachel C. Jankowitz: University of Pittsburgh School of Medicine
Esther M. John: Stanford University School of Medicine
Nichola Johnson: The Institute of Cancer Research
Vijai Joseph: Memorial Sloan-Kettering Cancer Center
Beth Y. Karlan: University of California at Los Angeles
Elza Khusnutdinova: Ufa Federal Research Centre of Russian Academy of Sciences
Johanna I. Kiiski: Helsinki University Hospital, University of Helsinki
Yon-Dschun Ko: Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus
Michael E. Jones: The Institute of Cancer Research
Irene Konstantopoulou: National Centre for Scientific Research ‘Demokritos’
Vessela N. Kristensen: Oslo University Hospital-Radiumhospitalet
Yael Laitman: Chaim Sheba Medical Center
Diether Lambrechts: VIB Center for Cancer Biology, VIB
Conxi Lazaro: ICO-IDIBELL (Bellvitge Biomedical Research Institute, Catalan Institute of Oncology), CIBERONC
Goska Leslie: University of Cambridge
Jenny Lester: University of California at Los Angeles
Fabienne Lesueur: Genetic Epidemiology of Cancer team, Inserm U900
Sara Lindström: University of Washington School of Public Health
Jirong Long: Vanderbilt University School of Medicine
Jennifer T. Loud: National Cancer Institute
Jan Lubiński: Pomeranian Medical University
Enes Makalic: The University of Melbourne
Arto Mannermaa: University of Eastern Finland
Mehdi Manoochehri: German Cancer Research Center (DKFZ)
Sara Margolin: Södersjukhuset
Tabea Maurer: University Medical Center Hamburg-Eppendorf
Dimitrios Mavroudis: University Hospital of Heraklion
Lesley McGuffog: University of Cambridge
Alfons Meindl: University of Munich, Campus Großhadern
Usha Menon: University College London
Kyriaki Michailidou: University of Cambridge
Austin Miller: Roswell Park Cancer Institute
Marco Montagna: Veneto Institute of Oncology IOV - IRCCS
Fernando Moreno: Centro Investigación Biomédica en Red de Cáncer (CIBERONC)
Lidia Moserle: Veneto Institute of Oncology IOV - IRCCS
Anna Marie Mulligan: University of Toronto
Katherine L. Nathanson: University of Pennsylvania
Susan L. Neuhausen: Beckman Research Institute of City of Hope
Heli Nevanlinna: Helsinki University Hospital, University of Helsinki
Ines Nevelsteen: University Hospitals Leuven
Finn C. Nielsen: Copenhagen University Hospital
Liene Nikitina-Zake: Latvian Biomedical Research and Study Centre
Robert L. Nussbaum: University of California San Francisco
Kenneth Offit: Memorial Sloan-Kettering Cancer Center
Edith Olah: National Institute of Oncology
Olufunmilayo I. Olopade: The University of Chicago
Håkan Olsson: Lund University
Ana Osorio: Centro de Investigación en Red de Enfermedades Raras (CIBERER)
Janos Papp: National Institute of Oncology
Tjoung-Won Park-Simon: Hannover Medical School
Michael T. Parsons: QIMR Berghofer Medical Research Institute
Inge Sokilde Pedersen: Aalborg University Hospital
Ana Peixoto: Portuguese Oncology Institute
Paolo Peterlongo: Genome Diagnostics Program, IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology
Paul D. P. Pharoah: University of Cambridge
Dijana Plaseska-Karanfilska: Macedonian Academy of Sciences and Arts
Bruce Poppe: Ghent University
Nadege Presneau: University of Westminster
Paolo Radice: Fondazione IRCCS Istituto Nazionale dei Tumori (INT)
Johanna Rantala: Karolinska Institutet
Gad Rennert: Carmel Medical Center and Technion Faculty of Medicine
Harvey A. Risch: Yale School of Public Health
Emmanouil Saloustros: University Hospital of Larissa
Kristin Sanden: City of Hope Clinical Cancer Genetics Community Research Network
Elinor J. Sawyer: Guy’s Hospital, King’s College London
Marjanka K. Schmidt: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Rita K. Schmutzler: University of Cologne
Priyanka Sharma: University of Kansas Medical Center
Xiao-Ou Shu: Vanderbilt University School of Medicine
Jacques Simard: Centre Hospitalier Universitaire de Québec – Université Laval, Research Center
Christian F. Singer: Medical University of Vienna
Penny Soucy: Centre Hospitalier Universitaire de Québec – Université Laval, Research Center
Melissa C. Southey: Monash University
John J. Spinelli: BC Cancer
Amanda B. Spurdle: QIMR Berghofer Medical Research Institute
Jennifer Stone: The University of Melbourne
Anthony J. Swerdlow: The Institute of Cancer Research
William J. Tapper: University of Southampton
Jack A. Taylor: NIH
Manuel R. Teixeira: Portuguese Oncology Institute
Mary Beth Terry: Columbia University
Alex Teulé: IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, CIBERONC
Mads Thomassen: Odense University Hospital
Kathrin Thöne: University Medical Center Hamburg-Eppendorf
Darcy L. Thull: University of Pittsburgh School of Medicine
Marc Tischkowitz: McGill University
Amanda E. Toland: The Ohio State University
Diana Torres: German Cancer Research Center (DKFZ)
Thérèse Truong: University Paris-Saclay
Nadine Tung: Beth Israel Deaconess Medical Center
Celine M. Vachon: Mayo Clinic
Christi J. Asperen: Leiden University Medical Center
Ans M. W. Ouweland: Erasmus University Medical Center
Elizabeth J. Rensburg: University of Pretoria
Ana Vega: CIBERER, IDIS
Alessandra Viel: Centro di Riferimento Oncologico di Aviano (CRO), IRCCS
Qin Wang: University of Cambridge
Barbara Wappenschmidt: University of Cologne
Jeffrey N. Weitzel: Clinical Cancer Genomics, City of Hope
Camilla Wendt: Södersjukhuset, Karolinska Institutet
Robert Winqvist: University of Oulu
Xiaohong R. Yang: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services
Drakoulis Yannoukakos: National Centre for Scientific Research ‘Demokritos’
Argyrios Ziogas: University of California Irvine
Peter Kraft: Harvard T.H. Chan School of Public Health
Antonis C. Antoniou: University of Cambridge
Wei Zheng: Vanderbilt University School of Medicine
Douglas F. Easton: University of Cambridge
Roger L. Milne: Cancer Council Victoria
Jonathan Beesley: QIMR Berghofer Medical Research Institute
Georgia Chenevix-Trench: QIMR Berghofer Medical Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08053-5

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