Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

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

Adult Cancer Program Lowy Cancer Research Centre University of NSW Sydney Sydney New South Wales Australia

Behavioral and Epidemiology Research Group American Cancer Society Atlanta GA USA

Biomedical Sciences Institute University of Porto Porto Portugal

Bioscience Department Faculty of Medicine Universidad de la Sabana Chia Colombia

Biostatistics and Computational Biology Branch National Institute of Environmental Health Sciences NIH Durham NC USA

Biostatistics Unit The Cyprus Institute of Neurology and Genetics Nicosia Cyprus

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

Cancer and Environment Group Center for Research in Epidemiology and Population Health INSERM University Paris Sud University of Paris Saclay Paris France

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Epidemiology Group University Cancer Center Hamburg University Medical Center Hamburg Eppendorf Hamburg Germany

Cancer Genetics and Prevention Program University of California San Francisco San Francisco CA USA

Cancer Prevention Program Fred Hutchinson Cancer Research Center Seattle WA USA

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

Cancer Sciences Academic Unit Faculty of Medicine University of Southampton Southampton UK

Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core Cedars Sinai Medical Center Los Angeles CA USA

Center for Clinical Cancer Genetics The University of Chicago Chicago IL USA

Center for Familial Breast and Ovarian Cancer Center for Integrated Oncology Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Medical Genetics NorthShore University HealthSystem Evanston IL 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 Cancer Genetic Epidemiology University of Cambridge Cambridge UK

Centre for Cancer Research and Cell Biology Queen's University Belfast Belfast Northern Ireland UK

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

Centre for Medical Genetics Ghent University Ghent Belgium

Centro de Investigación Biomédica en Red de Enfermedades Raras Valencia Spain

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

Chronic Disease Epidemiology Yale School of Public Health New Haven CT USA

CIBERER Santiago de Compostela Spain

Clalit National Cancer Control Center Carmel Medical Center and Technion Faculty of Medicine Haifa Israel

Clinical Cancer Genetics Program Division of Human Genetics Department of Internal Medicine Comprehensive Cancer Center The Ohio State University Columbus OH USA

Clinical Cancer Genomics City of Hope Duarte CA USA

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London UK

Clinical Genetics Karolinska Institutet Stockholm Sweden

Clinical Genetics Research Laboratory Department of Cancer Biology and Genetics Memorial Sloan Kettering Cancer Center New York NY USA

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark

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

Cyprus School of Molecular Medicine Nicosia Cyprus

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

David Geffen School of Medicine Department of Obstetrics and Gynecology University of California Los Angeles Los Angeles CA USA

Department of Anatomical Pathology The Alfred Hospital Melbourne Victoria Australia

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

Department of Biology University of Pisa Pisa Italy

Department of Biomedical Sciences Faculty of Science and Technology University of Westminster London UK

Department of Biostatistics Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Breast Medical Oncology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Cancer Biology and Genetics The Ohio State University Columbus OH USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Cancer Epidemiology and Prevention M Sklodowska Curie Cancer Center Oncology Institute Warsaw Poland

Department of Cancer Epidemiology Clinical Sciences Lund University Lund Sweden

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

Department of Clinical Biochemistry Herlev and Gentofte 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 PA USA

Department of Clinical Genetics Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Genetics Odense University Hospital Odense Denmark

Department of Clinical Pathology University of Melbourne Melbourne Victoria Australia

Department of Clinical Science and Education Södersjukhuset Karolinska Institutet Stockholm Sweden

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

Department of Epidemiology Genetic Epidemiology Research Institute University of California Irvine Irvine CA USA

Department of Epidemiology Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA USA

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

Department of Epidemiology The Netherlands Cancer Institute Amsterdam the Netherlands

Department of Family Medicine and Public Health School of Medicine University of California San Diego La Jolla CA USA

Department of Family Medicine and Public Health University of California San Diego La Jolla CA USA

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Department of Genetics and Fundamental Medicine Bashkir State Medical University Ufa Russia

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Genetics INSERM U830 Institut Curie Paris Descartes Sorbonne Paris Cité University Paris France

Department of Genetics Portuguese Oncology Institute Porto Portugal

Department of Genetics University of Pretoria Pretoria South Africa

Department of Gynaecology and Obstetrics University Hospital Erlangen Friedrich Alexander University Erlangen Nuremberg Comprehensive Cancer Center ER EMN Erlangen Germany

Department of Gynaecology and Obstetrics University Hospital Ulm Ulm Germany

Department of Gynecology and Obstetrics Comprehensive Cancer Center ER EMN University Hospital Erlangen Friedrich Alexander University of Erlangen Nuremberg Erlangen Germany

Department of Gynecology and Obstetrics Helios Clinics Berlin Buch Berlin Germany

Department of Gynecology and Obstetrics Ludwig Maximilian University of Munich Munich Germany

Department of Health Science Research Division of Epidemiology Mayo Clinic Rochester MN USA

Department of Health Sciences Research Mayo Clinic College of Medicine Jacksonville FL USA

Department of Human Genetics Leiden University Medical Center Leiden the Netherlands

Department of Internal Medicine Division of Oncology University of Kansas Medical Center Westwood Kansas City KS USA

Department of Internal Medicine Evangelische Kliniken Bonn Johanniter Krankenhaus Bonn Germany

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

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge UK

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

Department of Medical Oncology Family Cancer Clinic Erasmus MC Cancer Institute Rotterdam the Netherlands

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

Department of Medicine Division of Oncology Stanford Cancer Institute School of Medicine Stanford University Stanford CA USA

Department of Medicine Huntsman Cancer Institute Salt Lake City UT USA

Department of Medicine Magee Womens Hospital School of Medicine University of Pittsburgh Pittsburgh PA USA

Department of Medicine McGill University Montréal Québec Canada

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

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

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

Department of Oncology Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Oncology Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA

Department of Oncology Lund University and Skåne University Hospital Lund Sweden

Department of Oncology Örebro University Hospital Örebro Sweden

Department of Oncology School of Medicine Johns Hopkins University Baltimore MD USA

Department of Oncology Södersjukhuset Stockholm Sweden

Department of Oncology University Hospital of Larissa Larissa Greece

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

Department of Pathology Leiden University Medical Center Leiden the Netherlands

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

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

Department of Public Health Sciences and Cancer Research Institute Queen's University Kingston Ontario Canada

Department of Radiation Oncology Hannover Medical School Hannover Germany

Department of Surgery Leiden University Medical Center Leiden the Netherlands

Department of Surgical Oncology Family Cancer Clinic Erasmus MC Cancer Institute Rotterdam the Netherlands

Department of Surgical Pathology Zealand University Hospital Slagelse Denmark

Department of Surgical Sciences Uppsala University Uppsala Sweden

Department of Women's Health University of Tübingen Tübingen Germany

Departments of Pediatrics and Medicine Columbia University New York NY USA

Division of Breast Cancer Research The Institute of Cancer Research London UK

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Department of Health and Human Services Bethesda MD USA

Division of Cancer Epidemiology DKFZ Heidelberg Germany

Division of Cancer Prevention and Genetics European Institute of Oncology IRCCS Milan Italy

Division of Cancer Sciences University of Manchester Manchester UK

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

Division of Clinical Epidemiology Royal Victoria Hospital McGill University Montréal Québec Canada

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

Division of Evolution and Genomic Medicine School of Biological Sciences Faculty of Biology Medicine and Health University of Manchester Manchester Academic Health Science Centre Manchester UK

Division of Genetics and Epidemiology The Institute of Cancer Research London UK

Division of Informatics Imaging and Data Sciences Faculty of Biology Medicine and Health University of Manchester Manchester Academic Health Science Centre Manchester UK

Division of Molecular Pathology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Division of Preventive Oncology DKFZ and National Center for Tumor Diseases Heidelberg Germany

Division of Psychosocial Research and Epidemiology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Dr Margarete Fischer Bosch Institute of Clinical Pharmacology Stuttgart Germany

Epidemiology Branch National Institute of Environmental Health Sciences NIH Durham NC USA

Epigenetic and Stem Cell Biology Laboratory National Institute of Environmental Health Sciences NIH Durham NC USA

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Medicine University of Heidelberg Heidelberg Germany

Faculty of Medicine University of Southampton Southampton UK

Family Cancer Clinic The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Fred A Litwin Center for Cancer Genetics Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Toronto Ontario Canada

Genetic Epidemiology of Cancer Team INSERM U900 Institut Curie PSL University Mines ParisTech Paris France

Genetic Epidemiology of Cancer Team INSERM U900 Paris France

Genome Diagnostics Program IFOM FIRC Institute of Molecular Oncology Milan Italy

Genomic Medicine Group Galician Foundation of Genomic Medicine IDIS Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela Spain

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Center Québec City Québec Canada

German Cancer Consortium DKFZ Heidelberg Germany

Gynaecology Research Unit Hannover Medical School Hannover Germany

Hematology Oncology and Transfusion Medicine Center Department of Molecular and Regenerative Medicine Vilnius University Hospital Santariskiu Clinics Vilnius Lithuania

Human Cancer Genetics Programme Spanish National Cancer Research Centre Madrid Spain

iFIT Cluster of Excellence University of Tübingen Tübingen Germany

Imaging Center Department of Clinical Pathology Kuopio University Hospital Kuopio Finland

Immunology and Molecular Oncology Unit Veneto Institute of Oncology IRCCS Padua Italy

Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Szczecin Poland

Institute for Prevention and Occupational Medicine of the German Social Accident Insurance Ruhr University Bochum Bochum Germany

Institute of Biochemistry and Genetics Ufa Federal Research Centre of the Russian Academy of Sciences Ufa Russia

Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK

Institute of Clinical Medicine Faculty of Medicine University of Oslo Oslo Norway

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

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Human Genetics Pontificia Universidad Javeriana Bogota Colombia

Institute of Human Genetics University Hospital Erlangen Friedrich Alexander University Erlangen Nuremberg Comprehensive Cancer Center ER EMN Erlangen Germany

Institute of Medical Biometry and Epidemiology University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Pathology Staedtisches Klinikum Karlsruhe Karlsruhe Germany

Instituto de Investigación Sanitaria de Santiago de Compostela Santiago de Compostela Spain

Laboratory Medicine Program University Health Network Toronto Ontario Canada

Laboratory of Cancer Genetics and Tumor Biology Cancer and Translational Medicine Research Unit Biocenter Oulu University of Oulu Oulu Finland

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

Laboratory of Translational Genetics Department of Human Genetics University of Leuven Leuven Belgium

Latvian Biomedical Research and Study Centre Riga Latvia

Leuven Multidisciplinary Breast Center Department of Oncology Leuven Cancer Institute University Hospitals Leuven Leuven Belgium

Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA

Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA

Manchester Centre for Genomic Medicine St Mary's Hospital Manchester NIHR Biomedical Research Centre Manchester University Hospitals NHS Foundation Trust Manchester Academic Health Science Centre Manchester UK

Medical Oncology Department Hospital Clínico San Carlos Instituto de Investigación Sanitaria San Carlos Madrid Spain

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Molecular Biology of Breast Cancer University Women's Clinic Heidelberg University of Heidelberg Heidelberg Germany

Molecular Diagnostic Unit Hereditary Cancer Program Bellvitge Biomedical Research Institute CIBERONC Barcelona Spain

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

Molecular Epidemiology Group DKFZ Heidelberg Germany

Molecular Genetics of Breast Cancer DKFZ Heidelberg Germany

Molecular Medicine Unit Fundación Pública Galega de Medicina Xenómica Santiago de Compostela Spain

Moores Cancer Center University of California San Diego La Jolla CA USA

MRC Clinical Trials Unit at UCL Institute of Clinical Trials and Methodology University College London London UK

N N Alexandrov Research Institute of Oncology and Medical Radiology Minsk Belarus

N N Petrov Institute of Oncology St Petersburg Russia

National Human Genome Research Institute National Cancer Institute Bethesda MD USA

NCT University Hospital and DKFZ Heidelberg Germany

Nightingale Breast Screening Centre Wythenshawe Hospital Manchester University NHS Foundation Trust Manchester UK

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

Oncogenetics Group Vall d'Hebron Institute of Oncology Barcelona Spain

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Parkville Familial Cancer Centre Peter MacCallum Cancer Center Melbourne Victoria Australia

Peter MacCallum Cancer Center Melbourne Victoria Australia

Population Oncology BC Cancer Vancouver British Columbia Canada

Precision Medicine School of Clinical Sciences at Monash Health Monash University Melbourne Victoria Australia

Prevent Breast Cancer Centre and Nightingale Breast Screening Centre Manchester University NHS Foundation Trust Manchester UK

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montréal Québec Canada

Program in Genetic Epidemiology and Statistical Genetics Harvard T H Chan School of Public Health Boston MA USA

Radiation Epidemiology Branch Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Research Centre for Genetic Engineering and Biotechnology 'Georgi D Efremov' Macedonian Academy of Sciences and Arts Skopje Republic of Macedonia

Research Oncology Guy's Hospital King's College London London UK

Saarland Cancer Registry Saarbrücken Germany

School of Population and Public Health University of British Columbia Vancouver British Columbia Canada

School of Women's and Children's Health Faculty of Medicine University of NSW Sydney Sydney New South Wales Australia

Section of Molecular Genetics Department of Laboratory Medicine University Hospital of Pisa Pisa Italy

Sheffield Institute for Nucleic Acids Department of Oncology and Metabolism University of Sheffield Sheffield UK

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

Ss Cyril and Methodius University in Skopje Medical Faculty University Clinic of Radiotherapy and Oncology Skopje Republic of North Macedonia

State Research Institute Center for Innovative Medicine Vilnius Lithuania

The Kinghorn Cancer Centre Garvan Institute of Medical Research Sydney New South Wales Australia

The Susanne Levy Gertner Oncogenetics Unit Chaim Sheba Medical Center Ramat Gan Israel

Translational Cancer Research Area University of Eastern Finland Kuopio Finland

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

Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research INT Milan Italy

Université Paris Sorbonne Cité INSERM UMR S1147 Paris France

University of Tübingen Tübingen Germany

Usher Institute of Population Health Sciences and Informatics University of Edinburgh Medical School Edinburgh UK

VIB Center for Cancer Biology VIB Leuven Belgium

Waukesha Memorial Hospital Pro Health Care Waukesha WI USA

Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK

Westmead Institute for Medical Research University of Sydney Sydney New South Wales Australia

Zilber School of Public Health University of Wisconsin Milwaukee Milwaukee WI USA

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Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk