Genomic Structural Equation Modeling Identifies a Shared Inflammatory Genetic Dimension Across Inflammatory Arthritis Phenotypes and Biomarkers

ABSTRACT Background Inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout, shares systemic inflammatory features indexed by C‐reactive protein (CRP) and interleukin‐6 (IL‐6), yet the extent of their common genetic basis remains unclear. Aims We aimed to delineate the shared genetic architecture across IA phenotypes and inflammatory biomarkers. Materials and Methods We applied genomic structural equation modelling (Genomic SEM) to GWAS summary statistics for RA, PsA, gout, CRP and IL‐6, fitted a single common factor, and performed multivariate GWAS followed by fine‐mapping, transcriptome‐wide association, gene‐based analysis, pathway enrichment, and cell‐type and spatial mapping. Results A single common factor was fitted (CFI = 0.990, SRMR = 0.045). The multivariate GWAS identified 56 genome‐wide significant SNPs across 10 independent lead loci, including one novel signal. Fine‐mapping prioritized high‐confidence variants near PTPN22 , the CRP gene cluster and a urate‐associated locus. Gene‐level analyses converged on DCLRE1B , PTPN22 , IL6R , NLRP3 and HNF1A , with pathway enrichment implicating inflammasome assembly and metabolic‐inflammatory overlap. Cell‐type enrichment highlighted myeloid populations, and spatial mapping localized signals to lung, kidney, mucosal epithelium and gastrointestinal tissues. Discussion These results delineate a shared inflammatory genetic dimension across IA phenotypes and biomarkers, anchored in immune, inflammasome, cytokine‐receptor and metabolic pathways. Conclusion Together, these findings provide a valuable framework for prioritizing candidate genes and cellular contexts for future investigation.