Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 750-764 |
| Number of pages | 15 |
| Journal | Arthritis and Rheumatology |
| Volume | 77 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2025 |
Funding
Partially supported by the Training in Precision Environmental Health Sciences Training Program (fellowship T32‐ES‐027801). This research was supported in part by the Intramural Research Program of the NIH. This research was supported by the NIHR Manchester Biomedical Research Centre (grant 203308), the NIHR Great Ormond Street Hospital Biomedical Research Centre (grant 18474), Myositis UK (grant 20380), Great Ormond Street Children's Charity (grant 20164), Versus Arthritis (grant 21593), and Medical Research Council (grant MR/n003322/1). Dr Lundberg's work was supported by the Swedish Research Council (grant 2020‐01378), Region Stockholm Avtal om Läkarutbildning och Forskning (ALF project), the Swedish Rheumatism Association, and the King Gustaf V 80 Year Foundation. Dr Vencovsky's work was supported by the Czech Ministry of Health 00023728 (Institute of Rheumatology). Drs Han, Byun, Amos, and Wedderburn's work was supported by The Cure JM Foundation. The authors thank Drs Michael Ombrello, Elaine Remmers, and Sandeep Agarwal for useful comments on the manuscript. Jan L. De Bleecker is a member of the European Reference Network for Neuromuscular Diseases. The authors acknowledge minimal usage of ChatGPT and Grammarly for checking spelling and grammar. Citation style was generated using Schiwheel.
ASJC Scopus subject areas
- Immunology and Allergy
- Rheumatology
- Immunology
