Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

BHF Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Strangeways Research Laboratory Wort's Causeway Cambridge CB1 8RN UK

BHF Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Strangeways Research Laboratory Wort's Causeway Cambridge CB1 8RN UK Medical Research Council Biostatistics Unit Cambridge Institute of Public Health Cambridge Biomedical Campus Forvie Site Robinson Way Cambridge CB2 0SR UK NHS Blood and Transplant Long Road Cambridge Biomedical Campus Cambridge UK

Department of Autoimmune Diseases Hospital Clínic University of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer CRB CELLEX Barcelona Spain

Department of Biomedical Experimental and Clinical Sciences Mario Serio University of Firenze and Meyer Children's Hospital Firenze Italy

Department of Experimental and Clinical Medicine University of Firenze Firenze Italy

Department of Internal Medicine 3 Jena University Hospital Jena Germany Department of Internal Medicine 4 Jena University Hospital Jena Germany

Department of Internal Medicine 3 Jena University Hospital Jena Germany Department of Rheumatology Immunology and Rehabilitation Cantonal Hospital St Gallen St Gallen Switzerland

Department of Internal Medicine 3 Rheumatology and Immunology Friedrich Alexander University Erlangen Nuremberg and Universitatsklinikum Erlangen Erlangen Germany

Department of Medicine and Surgery Università degli Studi di Milano Bicocca via Cadore 48 20900 Monza Italy

Department of Medicine University of Cambridge School of Clinical Medicine University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0QQ UK

Department of Medicine University of Cambridge School of Clinical Medicine University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0QQ UK BHF Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Strangeways Research Laboratory Wort's Causeway Cambridge CB1 8RN UK Health Data Research UK Cambridge UK

Department of Medicine University of Cambridge School of Clinical Medicine University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0QQ UK Cambridge Institute for Therapeutic Immunology and Infectious Disease Jeffrey Cheah Biomedical Centre University of Cambridge Cambridge CB2 0AW UK

Department of Medicine University of Cambridge School of Clinical Medicine University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0QQ UK Cambridge Institute for Therapeutic Immunology and Infectious Disease Jeffrey Cheah Biomedical Centre University of Cambridge Cambridge CB2 0AW UK Medical Research Council Biostatistics Unit Cambridge Institute of Public Health Cambridge Biomedical Campus Forvie Site Robinson Way Cambridge CB2 0SR UK

Department of Medicine University of Cambridge School of Clinical Medicine University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0QQ UK Medical Research Council Biostatistics Unit Cambridge Institute of Public Health Cambridge Biomedical Campus Forvie Site Robinson Way Cambridge CB2 0SR UK

Department of Medicine University of Cambridge School of Clinical Medicine University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0QQ UK Nephrology and Immunopathology Unit ASST Santi Paolo e Carlo San Carlo Borromeo Hospital Milan Italy Dipartimento di Scienze della Salute University of Milano Milano Italy

Department of Nephrology 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

Department of Nephrology Division of Clinical Sciences Lund University Lund Sweden

Department of Rheumatology and Clinical Immunology University of Lübeck 23562 Lübeck Germany

Department of Rheumatology Ipswich Hospital Heath Road Ipswich Suffolk IP4 5PD UK Norwich Medical School University of East Anglia Norwich NR7 4TJ UK

Division of Rheumatology Department of Medicine Karolinska University Hospital Karolinska Institute Stockholm Sweden

Human Genetics Ruhr University Bochum Bochum Germany

Jagiellonian University Medical College Kraków Poland

Rheumatology Unit University of Pisa Pisa Italy

Rheumazentrum Schleswig Holstein Mitte Neumünster Germany

Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics University of Melbourne Parkville VIC 3010 Australia Data Science Murdoch Children's Research Institute Parkville VIC 3052 Australia

Service de Médecine Interne Hôpital Cochin 75679 Paris Cedex 14 France

The National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge University of Cambridge Strangeways Research Laboratory Wort's Causeway Cambridge CB1 8RN UK Department of Human Genetics The Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton Cambridge CB10 1HH UK

Trinity Health Kidney Centre Trinity Translational Medicine Institute Tallaght Hospital Dublin Ireland

Unit of Immunology Rheumatology Allergy and Rare Diseases Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele Milan Italy

Unit of Molecular Genetics University Hospital of Parma Via Gramsci 14 43126 Parma Italy