We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Abramson Cancer Center Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Academic Biochemistry Royal Marsden Hospital London UK

Academic Unit of Pathology Department of Neuroscience University of Sheffield Sheffield UK

Biomedical Network on Rare Diseases Madrid Spain

Biomedical Sciences Institute Porto University Porto Portugal

Breast Cancer and Systems Biology Unit IDIBELL Catalan Institute of Oncology Barcelona Spain

Breast Cancer Research Breakthrough Breast Cancer Research Centre London UK

Breast Cancer Research Unit University Malaya Cancer Research Institute University Malaya Medical Centre Kuala Lumpur Malaysia

Cancer Center Kuopio University Hospital Kuopio Finland

Cancer Division QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Cancer Epidemiology Centre Cancer Council Victoria Melbourne Victoria Australia

Cancer Research Initiatives Foundation Sime Darby Medical Centre Subang Jaya Malaysia

Cancer Research Institute Seoul National University College of Medicine Seoul Korea

Cancer Risk and Prevention Clinic Dana Farber Cancer Institute Boston Massachusetts USA

Cancer Science Institute of Singapore National University of Singapore Singapore

Center for Clinical Cancer Genetics and Global Health University of Chicago Medical Center Chicago Illinois USA

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Integrated Oncology University Hospital Cologne Germany

Center for Medical Genetics Ghent University Ghent Belgium

Center for Medical Genetics NorthShore University Health System Evanston Illinois USA

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Centre for Epidemiology and Biostatistics School of Population and Global Health University of Melbourne Melbourne Victoria Australia

Centre for Epidemiology and Biostatistics University of Melbourne Melbourne Victoria Australia

Centre for Genetic Origins of Health and Disease University of Western Australia Perth Western Australia Australia

Centre Hospitalier Universitaire de Québec and Laval University Quebec City Quebec Canada

Centre of Familial Breast and Ovarian Cancer Department of Gynaecology and Obstetrics and Centre for Integrated Oncology Center for Molecular Medicine Cologne University Hospital of Cologne Cologne Germany

Centre of Familial Breast and Ovarian Cancer University Hospital of Cologne Cologne Germany

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

City of Hope Clinical Cancer Genomics Community Research Network Duarte California USA

Clalit National Israeli Cancer Control Center Haifa Israel

Clinical Cancer Genetics City of Hope Duarte California USA

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute US National Institutes of Health Rockville Maryland USA

Clinical Genetics Guy's and St Thomas' National Health Service Foundation Trust London UK

Clinical Gerontology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology Cambridge Massachusetts USA

Copenhagen General Population Study Herlev Hospital Copenhagen University Hospital Herlev Denmark

Department of Basic Sciences Shaukat Khanum Memorial Cancer Hospital and Research Centre Lahore Pakistan

Department of Biomedical Sciences Seoul National University College of Medicine Seoul Korea

Department of Breast Surgery Herlev Hospital Copenhagen University Hospital Herlev Denmark

Department of Cancer Epidemiology Moffitt Cancer Center Tampa Florida USA

Department of Clinical Biochemistry Herlev Hospital Copenhagen University Hospital Herlev Denmark

Department of Clinical Genetics Erasmus University Medical Center Rotterdam the Netherlands

Department of Clinical Genetics Fox Chase Cancer Center Philadelphia Pennsylvania USA

Department of Clinical Genetics Helsinki University Central Hospital Helsinki Finland

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Genetics Lund University Hospital Lund Sweden

Department of Clinical Genetics Odense University Hospital Odense Denmark

Department of Clinical Genetics Vejle Hospital Vejle Denmark

Department of Clinical Molecular Biology Oslo University Hospital University of Oslo Oslo Norway

Department of Community Medicine and Epidemiology Carmel Medical Center and B Rappaport Faculty of Medicine Haifa Israel

Department of Dermatology Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City Utah USA

Department of Epidemiology Cancer Prevention Institute of California Fremont California USA

Department of Epidemiology Harvard School of Public Health Boston Massachusetts USA

Department of Epidemiology Mailman School of Public Health Columbia University New York New York USA

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Epidemiology Shanghai Cancer Institute Shanghai China

Department of Epidemiology University of California Irvine Irvine California USA

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Genetics Institute for Cancer Research Oslo University Hospital Radiumhospitalet Oslo Norway

Department of Genetics Portuguese Oncology Institute Porto Portugal

Department of Genetics Stanford University School of Medicine Stanford California USA

Department of Genetics University of Pretoria Pretoria South Africa

Department of Gynaecology and Obstetrics Technical University of Munich Munich Germany

Department of Gynaecology and Obstetrics University Hospital of Schleswig Holstein Campus Kiel Christian Albrechts University Kiel Kiel Germany

Department of Gynecology and Obstetrics University Hospital Erlangen Friedrich Alexander University Erlangen Nuremberg Comprehensive Cancer Center Erlangen Nuremberg Metropolitan Region Erlangen Germany

Department of Haematology Oncology National University Health System Singapore

Department of Health Sciences Research Mayo Clinic Rochester Minnesota USA

Department of Human Genetics Leiden University Medical Center Leiden the Netherlands

Department of Human Genetics Radboud University Nijmegen Medical Centre Nijmegen the Netherlands

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Oncology Beth Israel Deaconess Medical Center Boston Massachusetts USA

Department of Medical Oncology Erasmus University Medical Center Rotterdam the Netherlands

Department of Medical Oncology Family Cancer Clinic Erasmus University Medical Center Rotterdam the Netherlands

Department of Medicine and Genetics University of California San Francisco San Francisco California USA

Department of Medicine Division of Hematology and Oncology David Geffen School of Medicine University of California Los Angeles Los Angeles California USA

Department of Medicine Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City Utah USA

Department of Medicine McGill University Montreal Quebec Canada

Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Molecular Genetics University of Toronto Toronto Ontario Canada

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Molecular Medicine University La Sapienza Rome Italy

Department of Molecular Virology Immunology and Medical Genetics Comprehensive Cancer Center The Ohio State University Columbus Ohio USA

Department of Non Communicable Disease Epidemiology London School of Hygiene and Tropical Medicine London UK

Department of Obstetrics and Gynecology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Obstetrics and Gynecology University of Heidelberg Heidelberg Germany

Department of Obstetrics and Gynecology University of Helsinki and Helsinki University Central Hospital Helsinki Finland

Department of Obstetrics Gynaecology and Pediatrics Dalhousie University Halifax Nova Scotia Canada

Department of Oncology Helsinki University Central Hospital University of Helsinki Helsinki Finland

Department of Oncology Lund University Lund Sweden

Department of Oncology Pathology Karolinska University Hospital Stockholm Sweden

Department of Oncology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City Kansas USA

Department of Pathology Landspitali University Hospital and Biomedical Centre Faculty of Medicine University of Iceland Reykjavik Iceland

Department of Pathology Leiden University Medical Center Leiden the Netherlands

Department of Pathology University of Melbourne Melbourne Victoria Australia

Department of Population Sciences Beckman Research Institute of City of Hope Duarte California USA

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles California USA

Department of Preventive Medicine Seoul National University College of Medicine Seoul Korea

Department of Surgery National University Health System Singapore

Department of Surgery University of Hong Kong Hong Kong

Division of Breast Cancer Research Institute of Cancer Research London UK

Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville Maryland USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Cancer Medicine Peter MacCallum Cancer Centre East Melbourne Victoria Australia

Division of Cancer Prevention and Control Research Jonsson Comprehensive Cancer Center University of California Los Angeles School of Medicine and School of Public Health Los Angeles California USA

Division of Cancer Prevention and Genetics Istituto Europeo di Oncologia Milan Italy

Division of Cancer Studies Breakthrough Breast Cancer Research Centre Institute of Cancer Research London UK

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology Royal Victoria Hospital McGill University Montreal Quebec Canada

Division of Epidemiology and Prevention Aichi Cancer Center Research Institute Aichi Japan

Division of Epidemiology Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

Division of Epidemiology Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville Tennessee USA

Division of Genetics and Epidemiology Institute of Cancer Research London UK

Division of Health Sciences Warwick Medical School Warwick University Coventry UK

Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

Division of Molecular Gyneco Oncology Department of Gynaecology and Obstetrics University Hospital of Cologne Cologne Germany

Division of Molecular Medicine Aichi Cancer Center Research Institute Nagoya Japan

Dr Margarete Fischer Bosch Institute of Clinical Pharmacology Stuttgart Germany

Environmental Epidemiology of Cancer Center for Research in Epidemiology and Population Health INSERM Villejuif France

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Familial Cancer Centre Peter MacCallum Cancer Centre Melbourne Victoria Australia

Genetic Counseling Unit Hereditary Cancer Program IDIBGI Catalan Institute of Oncology Girona Spain

German Cancer Consortium German Cancer Research Center Heidelberg Germany

Gynaecology Research Unit Hannover Medical School Hannover Germany

Hong Kong Hereditary Breast Cancer Family Registry Cancer Genetics Center Hong Kong Sanatorium and Hospital Hong Kong

Human Cancer Genetics Program Spanish National Cancer Centre Madrid Spain

Human Genetics Group Spanish National Cancer Centre Madrid Spain

Human Genotyping Madrid Spain

IFOM Fondazione Istituto FIRC di Oncologia Molecolare Milan Italy

Imaging Center Department of Clinical Pathology Kuopio University Hospital Kuopio Finland

Immunology and Molecular Oncology Unit Istituto Oncologico Veneto Padua Italy

INSERM U1052 CNRS UMR 5286 Université Lyon Centre de Recherche en Cancérologie de Lyon Lyon France

Institut Curie Department of Tumour Biology Paris France

Institute of Clinical Medicine Pathology and Forensic Medicine University of Eastern Finland Kuopio Finland

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Human Genetics Münster Germany

Institute of Human Genetics Pontificia Universidad Javerianar Bogota Colombia

Institute of Population Health University of Manchester Manchester UK

International Agency for Research on Cancer Lyon France

International Epidemiology Institute Rockville Maryland USA

Laboratory for Translational Genetics Department of Oncology University of Leuven Leuven Belgium

Laboratory Medicine Program University Health Network Toronto Ontario Canada

Laboratory of Cancer Genetics and Tumor Biology Department of Clinical Chemistry and Biocenter Oulu University of Oulu NordLab Oulu University Hospital Oulu Finland

Laboratory of Cancer Genetics and Tumor Biology Northern Finland Laboratory Centre NordLab Oulu Finland

Latvian Biomedical Research and Study Centre Riga Latvia

Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada

Masaryk Memorial Cancer Institute and Medical Faculty Masaryk University Brno Czech Republic

Medical Genetic Division Centre Hospitalier Universitaire de Québec and Laval University Quebec City Quebec Canada

Molecular Diagnostics Laboratory INRASTES National Centre for Scientific Research 'Demokritos' Aghia Paraskevi Attikis Athens Greece

Molecular Epidemiology Group German Cancer Research Center Heidelberg Germany

Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany

Molecular Oncology Laboratory Hospital Clinico San Carlos IdISSC Madrid Spain

Multidisciplinary Breast Center Department of General Medical Oncology University Hospitals Leuven Leuven Belgium

N N Petrov Institute of Oncology St Petersburg Russia

National Cancer Institute Bangkok Thailand

National Center for Tumor Diseases University of Heidelberg Heidelberg Germany

Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

NRG Oncology Statistics and Data Management Center Roswell Park Cancer Institute Buffalo New York USA

Oncogenetics Laboratory Vall d'Hebron Institute of Oncology Vall d'Hebron University Hospital Barcelona Spain

Oxford Biomedical Research Centre University of Oxford Oxford UK

Program in Cancer Genetics McGill University Montreal Quebec Canada

Program in Genetic Epidemiology and Statistical Genetics Harvard School of Public Health Boston Massachusetts USA

Prosserman Centre for Health Research Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada

Radiation Oncology Research Unit Hannover Medical School Hannover Germany

Research Oncology Division of Cancer Studies King's College London Guy's Hospital London UK

Roswell Park Cancer Institute Buffalo New York USA

Saw Swee Hock School of Public Health National University of Singapore Singapore

School of Public Health China Medical University Taichung Taiwan

Section of Genetic Oncology Department of Laboratory Medicine University of Pisa and University Hospital of Pisa Pisa Italy

Servicio de Cirugía General y Especialidades Hospital Monte Naranco Oviedo Spain

Sheffield Cancer Research Department of Oncology University of Sheffield Sheffield UK

Sir Peter MacCallum Department of Oncology University of Melbourne Melbourne Victoria Australia

State Research Institute Centre for Innovative Medicine Vilnius Lithuania

Susanne Levy Gertner Oncogenetics Unit Sheba Medical Center Tel Hashomer Israel

Taiwan Biobank Institute of Biomedical Sciences Academia Sinica Taipei Taiwan

Unit of Medical Genetics Department of Biomedical Experimental and Clinical Sciences University of Florence Florence Italy

Unit of Medical Genetics Department of Preventive and Predictive Medicine Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori Milan Italy

Unit of Molecular Basis of Genetic Risk and Genetic Testing Department of Preventive and Predictive Medicine Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents Hospices Civils de Lyon Centre Léon Bérard Lyon France

Université Paris Descartes Sorbonne Paris Cité Paris France

University Cancer Center Hamburg University Medical Center Hamburg Eppendorf Hamburg Germany

University Düsseldorf Dusseldorf Germany

University Malaya Cancer Research Institute Faculty of Medicine University Malaya Medical Centre University Malaya Kuala Lumpur Malaysia

University of Hawaii Cancer Center Honolulu Hawaii USA

University of Texas MD Anderson Cancer Center Houston Texas USA

University of Tübingen Tübingen Germany

University Paris Sud Villejuif France

Vesalius Research Center Leuven Belgium

Wellcome Trust Centre for Human Genetics University of Oxford Oxford UK

Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles California USA

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