OBJECTIVES: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. RESULTS: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. CONCLUSIONS: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.

Arthritis Research UK Centre for Adolescent Rheumatology and Institute of Child Health University College London London UK

Arthritis Research UK NIHR Manchester Musculoskeletal Biomedical Research Unit Central Manchester NHS Foundation Trust Manchester Academic Health Science Centre University of Manchester Manchester UK

Centre for Genetics and Genomics Arthritis Research UK University of Manchester Manchester UK

Centre for Integrated Genomic Medical Research University of Manchester Manchester UK

Department of Internal Medicine Vall d'Hebron Hospital Barcelona Spain

Department of Medicine University of Padova Padova Italy

Department of Musculoskeletal Biology Institute of Ageing and Chronic Disease University of Liverpool Liverpool UK

Department of Neurology Neuromuscular Reference Centre Ghent University Hospital Ghent Belgium

Department of Pediatrics Duke University Durham North Carolina USA

Department of Rheumatology and Center of Experimental Rheumatology University Hospital Zurich Zurich Switzerland

Department of Rheumatology and Clinical Immunology University Medical Center Utrecht Utrecht The Netherlands

Department of Rheumatology Oslo University Hospital Oslo Norway

Division of Clinical Immunology Department of Internal Medicine University of Debrecen Debrecen Hungary

Environmental Autoimmunity Group Clinical Research Branch National Institute of Environmental Health Science National Institutes of Health Bethesda Maryland USA

Geisel School of Medicine Dartmouth College Hanover New Hampshire USA

Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt Neuherberg Germany

Institute of Human Genetics Technische Universität München Munich Germany Institute of Human Genetics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Rheumatology and Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

MRC Centre for Neuromuscular Diseases UCL Institute of Neurology London UK

National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit Centre for Musculoskeletal Research University of Manchester Manchester UK

Neurologische Klinik und Poliklinik Klinikum rechts der Isar Technische Universität München Munich Germany Institute of Neurogenomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Northwestern University Feinberg School of Medicine and Ann and Robert H Lurie Children's Hospital of Chicago Chicago Illinois USA

Paediatric Department Naestved Hospital Næstved Denmark

Pitié Salpêtrière Hospital UPMC APHP Paris France

Rheumatology Unit Department of Medicine Karolinska University Hospital Karolinska Institutet Stockholm Sweden

Royal Adelaide Hospital and University of Adelaide Adelaide South Australia Australia

The Robert S Boas Center for Genomics and Human Genetics Feinstein Institute for Medical Research Manhasset New York USA

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Discovery of new myositis genetic associations through leveraging other immune-mediated diseases

Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies

Idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

The EuroMyositis registry: an international collaborative tool to facilitate myositis research

Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum