Zhu Catherine, Han Younghun, Byun Jinyoung, Xiao Xiangjun, Rothwell Simon, Miller Frederick W, Lundberg Ingrid E, Gregersen Peter K, Vencovsky Jiri, Shaw Vikram R, McHugh Neil, Limaye Vidya, Selva-O'Callaghan Albert, Hanna Michael G, Machado Pedro M, Pachman Lauren M, Reed Ann M, Rider Lisa G, Molberg Øyvind, Benveniste Olivier, Radstake Timothy, Doria Andrea, De Bleecker Jan L, De Paepe Boel, Maurer Britta, Ollier William E, Padyukov Leonid, Wedderburn Lucy R, Chinoy Hector, Lamb Janine A, Amos Christopher I
Baylor College of Medicine, Houston, Texas.
The University of Manchester, Manchester, United Kingdom.
Arthritis Rheumatol. 2025 Jun;77(6):750-764. doi: 10.1002/art.43088. Epub 2025 Feb 13.
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.
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.
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.
Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.
特发性炎症性肌病（IIM，肌炎）是罕见的系统性自身免疫性疾病，可导致肌肉炎症、无力及肌肉外表现，有强大的遗传成分影响疾病的发生发展。既往全基因组关联研究确定了与IIM相关的基因座。在本研究中，我们对来自两项既往全基因组肌炎研究的数据进行了填充，并分析了迄今为止最大的肌炎数据集，以确定与IIM及其临床亚型相关的新风险基因座和易感基因。
我们对14903名个体（3206例患者和11697名对照）进行了关联分析，这些个体具有来自精准医学跨组学参考面板的基因型和填充数据。在与肌炎相关的组织中进行精细定位和表达定量性状基因座共定位分析，以确定潜在的因果变异。使用带重启的随机游走（RWR）算法进行功能注释和网络分析，探索潜在的遗传网络和药物再利用机会。
我们的分析确定了新的风险基因座和易感基因，如总体IIM中的FCRLA、NFKB1、IRF4、DCAKD和ATXN2；多发性肌炎中的NEMP2；皮肌炎中的ACBC11；以及抗组氨酰 - 转运RNA合成酶自身抗体（抗Jo - 1）阳性的肌炎中的PSD3。我们还描述了HLA区域变异的影响以及C4的作用。共定位分析表明，DCAKD在皮肤和肌肉中、HCP5在肺中、IRF4在爱泼斯坦 - 巴尔病毒（EBV）转化的淋巴细胞、肺和全血中存在假定的因果变异。RWR进一步确定了其他候选基因的优先级，包括APP、CD74、CIITA、NR1H4和TXNIP，以供未来研究。
我们的研究揭示了导致IIM的新遗传区域，增进了我们对肌炎发病机制的理解，并为未来研究提供了新的见解。
