Abstract Objectives This study aimed to address the lack of gene expression regulation data in synovial tissues and to identify conditionally independent genes associated with rheumatoid arthritis (RA) in the synovium, a primary target tissue for RA. Methods Gene expression prediction models were built for synovial tissue using matched genotype and gene expression data from 202 subjects. Using this model, we conducted transcriptome-wide association study (TWAS), utilizing the largest RA genome-wide association study (GWAS) meta-analysis data (n = 276 020). Further analyses, including conditional and joint analysis, causal analysis, differential expression analysis and gene-set enrichment analysis, were conducted to deepen our understanding of genetic architecture and comorbidity aetiology of RA. Results Our analysis identified eight genes associated with RA, including three novel genes: TPRA1 (PTWAS = 9.59 × 1 0 −6), HIP1 (PTWAS = 1.47 × 1 0 −5), and RP11-73E17.2 (PTWAS = 3.32 × 1 0 −7). These genes differed from those identified in previous TWAS studies using alternative tissues, may play a crucial role in the target synovial tissue. We found four genes exhibited significant causal relationships with RA and were differentially expressed in RA patients. Furthermore, we explored potential drug repurposing opportunities for these genes. Conclusions Our study is the first to model gene expression in synovial tissue, uncovering novel genetic determinants of RA. This advancement not only deepens our understanding of RA's genetic architecture, but also offers promising avenues for targeted therapies and drug repurposing.

Synovial transcriptome-wide association study implicates novel genes underlying rheumatoid arthritis risk