OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

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

Baylor College of Medicine Houston Texas

Charles University Prague Czech Republic

Duke University Durham North Carolina

Ghent University Ghent Belgium

Karolinska Institutet and Karolinska University Hospital Stockholm Sweden

Manchester Metropolitan University Manchester United Kingdom

National Institute of Environmental Health Sciences NIH Bethesda Maryland

NIHR Biomedical Research Centre at Great Ormond Street Hospital Centre for Adolescent Rheumatology Versus Arthritis and University College London London United Kingdom

NIHR Manchester Biomedical Research Centre Manchester University NHS Foundation Trust and The University of Manchester Manchester United Kingdom and Salford Royal Hospital Northern Care Alliance NHS Foundation Trust and Manchester Academic Health Science Centre Salford United Kingdom

Oslo University Hospital Oslo Norway

Sorbonne Université AP HP Myology Research Center UMR974 Pitié Salpêtrière Hospital Paris France

The Feinstein Institute Manhasset New York

The University of Manchester Manchester United Kingdom

Universitat Autonoma de Barcelona Barcelona Spain

University College London London United Kingdom

University Hospital Bern Switzerland

University Medical Center Utrecht Utrecht The Netherlands

University of Adelaide Adelaide South Australia Australia

University of Bath Bath United Kingdom

University of Padova Padova Italy

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