OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

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

Baylor College of Medicine Houston Texas

Centre for Genetics and Genomics Versus Arthritis Centre for Musculoskeletal Research Faculty of Biology Medicine and Health University of Manchester Manchester UK

Department of Internal Medicine and Clinical Immunology Pitié Salpêtrière Hospital Paris France

Department of Neurology Ghent University Ghent Belgium

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology and Centre for Rheumatology UCL Division of Medicine University College London London UK

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London UK

Department of Pediatrics Duke University Durham North Carolina

Department of Pharmacy and Pharmacology University of Bath Bath UK

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

Department of Rheumatology and Immunology University Hospital Bern Switzerland

Department of Rheumatology Oslo University Hospital Oslo Norway

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Environmental Autoimmunity Group National Institute of Environmental Health Sciences NIH Bethesda Maryland

Epidemiology and Public Health Group Division of Population Health Health Services Research and Primary Care Faculty of Biology Medicine and Health University of Manchester Manchester UK

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

Internal Medicine Department Vall d'Hebron General Hospital Universitat Autonoma de Barcelona Barcelona Spain

Manchester Metropolitan University School of Healthcare Sciences Manchester UK

National Institute for Health Research Manchester Biomedical Research Centre Manchester University NHS Foundation Trust The University of Manchester Manchester UK and Department of Rheumatology Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Manchester Academic Health Science Centre Salford UK and Centre for Musculoskeletal Research Faculty of Biology Medicine and Health The University of Manchester Manchester UK

NIHR Biomedical Research Centre at Great Ormond Street Hospital and Arthritis Research UK Centre for Adolescent Rheumatology UCL Great Ormond Street Institute of Child Health University College London London UK

Paediatric Department Slagelse Hospital and Paediatric Rheumatology Unit Rigshospitalet Copenhagen Denmark

Rheumatology Unit Department of Medicine University of Padova Padova Italy

Rheumatology Unit Royal Adelaide Hospital and Discipline of Medicine Adelaide University Adelaide Australia

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

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Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses

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