Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

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Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype ^{1–
3}. To identify novel loci, we performed a genome-wide association study (GWAS) 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 (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) 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 (FDR) <0.05). Five loci showed associations ( P<0.05) in opposite directions between luminal- and non-luminal subtypes. In-silico analyses showed 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 37.6% for triple-negative and 54.2% for luminal A-like disease. The odds ratios of polygenic risk scores (PRSs), which included 330 variants, for the highest 1% quantiles compared to 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.

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Most cited references 35

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LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

Hilary Finucane, Stephan Ripke, Nick Patterson … (2015)

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

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Is Open Access

METAL: fast and efficient meta-analysis of genomewide association scans

Cristen Willer, Yun Li, Gonçalo R Abecasis (2010)

Summary: METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats. Availability and implementation: METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/ Contact: goncalo@umich.edu

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An Atlas of Genetic Correlations across Human Diseases and Traits

Brendan Bulik-Sullivan, Hilary Finucane, Verneri Anttila … (2015)

Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique – cross-trait LD Score regression – for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity and associations between educational attainment and several diseases. These results highlight the power of genome-wide analyses, since there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 19 March 2020

Publication date (Electronic): 18 May 2020

Publication date (Print): June 2020

Publication date PMC-release: 14 January 2021

Volume: 52

Issue: 6

Pages: 572-581

Affiliations

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

[2 ]Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA,

[3 ]Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK,

[4 ]Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia,

[5 ]Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA,

[6 ]Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK,

[7 ]Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel,

[8 ]Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland,

[9 ]Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada,

[10 ]Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA,

[11 ]Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany,

[12 ]Department of Public Health Sciences, and Cancer Research Institute, Queen’s University, Kingston, ON, Canada,

[13 ]Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,

[14 ]Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,

[15 ]Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA,

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

[17 ]Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK,

[18 ]Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,

[19 ]Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany,

[20 ]Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany,

[21 ]Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain,

[22 ]Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia,

[23 ]Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland,

[24 ]Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain,

[25 ]Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain,

[26 ]Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain,

[27 ]Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland,

[28 ]Department of Oncology, Örebro University Hospital, Örebro, Sweden,

[29 ]N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus,

[30 ]Gynaecology Research Unit, Hannover Medical School, Hannover, Germany,

[31 ]Department of Radiation Oncology, Hannover Medical School, Hannover, Germany,

[32 ]Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark,

[33 ]Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark,

[34 ]Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark,

[35 ]Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain,

[36 ]Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy,

[37 ]Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden,

[38 ]Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany,

[39 ]iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany,

[40 ]German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany,

[41 ]Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany,

[42 ]Bioscience Department, Faculty of Medicine, Universidad de la Sabana, Chia, Colombia,

[43 ]Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands,

[44 ]Department of Women’s Health, University of Tübingen, Tübingen, Germany,

[45 ]Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany,

[46 ]Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany,

[47 ]Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany,

[48 ]Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA,

[49 ]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,

[50 ]Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain,

[51 ]Section of Molecular Genetics, Dept. of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy,

[52 ]Department of Biology, University of Pisa, Pisa, Italy,

[53 ]Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain,

[54 ]Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany,

[55 ]Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium,

[56 ]Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA,

[57 ]Centre for Medical Genetics, Ghent University, Gent, Belgium,

[58 ]Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia,

[59 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA,

[60 ]Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK,

[61 ]Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK,

[62 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden,

[63 ]Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA,

[64 ]Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands,

[65 ]Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,

[66 ]Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA,

[67 ]Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK,

[68 ]Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK,

[69 ]Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany,

[70 ]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,

[71 ]David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA,

[72 ]Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK,

[73 ]Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic,

[74 ]Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research “Demokritos”, Athens, Greece,

[75 ]The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel,

[76 ]Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain,

[77 ]Moores Cancer Center, University of California San Diego, La Jolla, CA, USA,

[78 ]Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA,

[79 ]Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA,

[80 ]Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA,

[81 ]Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia,

[82 ]Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia,

[83 ]Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia,

[84 ]Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, USA,

[85 ]Department of Medicine, McGill University, Montréal, QC, Canada,

[86 ]Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada,

[87 ]Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia,

[88 ]Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA,

[89 ]Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA,

[90 ]Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France,

[91 ]Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany,

[92 ]Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany,

[93 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA,

[94 ]Waukesha Memorial Hospital-Pro Health Care, Waukesha, WI, USA,

[95 ]Department of Oncology, Södersjukhuset, Stockholm, Sweden,

[96 ]Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany,

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

[98 ]Nightingale Breast Screening Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK,

[99 ]Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands,

[100 ]Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands,

[101 ]Saarland Cancer Registry, Saarbrücken, Germany,

[102 ]Division of Cancer Sciences, University of Manchester, Manchester, UK,

[103 ]Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA,

[104 ]N.N. Petrov Institute of Oncology, St. Petersburg, Russia,

[105 ]A full list of authors can be found in the Supplementary Note,

[106 ]Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA,

[107 ]Clinical Genetics, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK,

[108 ]Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov”, Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia,

[109 ]Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland,

[110 ]Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia,

[111 ]Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania,

[112 ]4/30/01, Vilnius, Lithuania,

[113 ]Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany,

[114 ]Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA,

[115 ]Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK,

[116 ]Faculty of Medicine University of Heidelberg, Heidelberg, Germany,

[117 ]David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA,

[118 ]Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland,

[119 ]Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia,

[120 ]Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA,

[121 ]Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany,

[122 ]Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands,

[123 ]Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway,

[124 ]Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway,

[125 ]Depastment of Surgical Pathology, Zealand University Hospital, Slagelse, Denmark,

[126 ]VIB Center for Cancer Biology, VIB, Leuven, Belgium,

[127 ]Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium,

[128 ]Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden,

[129 ]Department of Surgical Sciences, Uppsala University, Uppsala, Sweden,

[130 ]Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris, France,

[131 ]Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Bellvitge Biomedical Research Institute, Catalan Institute of Oncology), CIBERONC, Barcelona, Spain,

[132 ]Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of North Macedonia,

[133 ]Genetic Epidemiology of Cancer team, Inserm U900, Paris, France,

[134 ]Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden,

[135 ]Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden,

[136 ]Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland,

[137 ]University of Tübingen, Tübingen, Germany,

[138 ]Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland,

[139 ]Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland,

[140 ]Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland,

[141 ]Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden,

[142 ]Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA,

[143 ]Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy,

[144 ]Department of Anatomical Pathology, The Alfred Hospital, Prahran, Victoria, Australia,

[145 ]Genetic Epidemiology of Cancer team, Inserm U900, Institut Curie, PSL University, Mines ParisTech, Paris, France,

[146 ]Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany,

[147 ]MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK,

[148 ]NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA,

[149 ]Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia,

[150 ]Laboratory Medicine Program, University Health Network, Toronto, ON, Canada,

[151 ]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada,

[152 ]Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA,

[153 ]Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark,

[154 ]Latvian Biomedical Research and Study Centre, Riga, Latvia,

[155 ]Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA,

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

[157 ]Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,

[158 ]Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary,

[159 ]Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA,

[160 ]Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia,

[161 ]Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden,

[162 ]Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,

[163 ]Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, Ireland, UK,

[164 ]Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences,, University of Florence, Florence, Italy,

[165 ]Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia,

[166 ]Department of Genetics, Portuguese Oncology Institute, Porto, Portugal,

[167 ]Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA,

[168 ]Genome Diagnostics Program, IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy,

[169 ]Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK,

[170 ]Peter MacCallum Cancer Center, Melbourne, Victoria, Australia,

[171 ]Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia,

[172 ]Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy,

[173 ]Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia,

[174 ]School of Women’s and Children’s Health, Faculty of Medicine, University of NSW Sydney, Sydney, New South Wales, Australia,

[175 ]The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia,

[176 ]Clinical Genetics, Karolinska Institutet, Stockholm, Sweden,

[177 ]Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan,

[178 ]Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA,

[179 ]Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain,

[180 ]Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal,

[181 ]Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands,

[182 ]Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany,

[183 ]Department of Oncology, University Hospital of Larissa, Larissa, Greece,

[184 ]Prevent Breast Cancer Centre and Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust, Manchester, UK,

[185 ]Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA,

[186 ]Research Oncology, Guy’s Hospital, King’s College London, London, UK,

[187 ]Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA,

[188 ]National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany,

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

[190 ]Department of Internal Medicine, Division of Oncology, University of Kansas Medical Center, Westwood, KS, USA,

[191 ]Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, FL, USA,

[192 ]Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA,

[193 ]Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria,

[194 ]Genomics Center, Centre Hospitalier Universitaire de Québec – Université Laval, Research Center, Québec City, QC, Canada,

[195 ]Population Oncology, BC Cancer, Vancouver, BC, Canada,

[196 ]School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada,

[197 ]The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, Australia,

[198 ]Department of Genetics, Inserm U830, Institut Curie, Paris Descartes Sorbonne-Paris-Cité University, Paris, France,

[199 ]Division of Breast Cancer Research, The Institute of Cancer Research, London, UK,

[200 ]National Human Genome Research Institute, National Cancer Institute, Bethesda, MD, USA,

[201 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA,

[202 ]Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA,

[203 ]Faculty of Medicine, University of Southampton, Southampton, UK,

[204 ]Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA,

[205 ]Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA,

[206 ]Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark,

[207 ]Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,

[208 ]Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada,

[209 ]Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK,

[210 ]Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA,

[211 ]Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands,

[212 ]Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK,

[213 ]Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK,

[214 ]Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia,

[215 ]Department of Epidemiology, Gilliungs School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA,

[216 ]Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA,

[217 ]Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany,

[218 ]Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA,

[219 ]Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands,

[220 ]Department of Genetics, University of Pretoria, Arcadia, South Africa,

[221 ]Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA,

[222 ]Clinical Cancer Genomics, City of Hope, Duarte, CA, USA,

[223 ]Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland,

[224 ]Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland,

[225 ]Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada,

[226 ]Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands,

[227 ]Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,

[228 ]Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus,

[229 ]Cyprus School of Molecular Medicine, Nicosia, Cyprus,

[230 ]Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands,

[231 ]Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

Author notes

[*]

Contributed equally

[**]

Jointly supervised this work

Corresponding Author: Nilanjan Chatterjee, 615 N. Wolfe Street, Room E3612, Baltimore, Maryland 21205, nchatte2@ 123456jhu.edu

Article

Manuscript ID: NIHMS1572778

DOI: 10.1038/s41588-020-0609-2

PMC ID: 7808397

PubMed ID: 32424353

SO-VID: 419fde8e-505f-4774-90e9-cca6933ef69f

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Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

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Most cited references 35

LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

METAL: fast and efficient meta-analysis of genomewide association scans

An Atlas of Genetic Correlations across Human Diseases and Traits

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