Genome‐Wide Association Analysis and Multi‐Omic Mendelian Randomization Insight Into the Molecular Network of Immune‐Related Dysfunction in the Pathogenesis of Rheumatoid Arthritis

Background Rheumatoid arthritis ( RA ) is a complex autoimmune disease influenced by genetic and immune dysregulation. The causal roles of specific immune‐related genes in RA pathogenesis remain incompletely understood. Methods We conducted a large‐scale genome‐wide association study ( GWAS ) meta‐analysis across three RA cohorts to identify genome‐wide significant risk loci. Causal genes and proteins were prioritized by integrating these results with cis‐ eQTL and pQTL datasets using two‐sample Mendelian randomization ( MR ) and summary‐data‐based MR ( SMR ). Cell‐type‐specific expression was assessed using single‐cell RNA sequencing ( scRNA ‐seq), and gene expression in RA synovial tissue was validated via bulk RNA ‐seq. Results We identified 29 independent RA ‐associated loci, including 7 novel associations. Integrated MR and SMR analyses classified ERAP2 as a high‐confidence causal gene, while SWAP70 and LTBR were deemed moderate‐confidence causal genes. SWAP70 showed a protective association, whereas ERAP2 and LTBR were positively associated with RA risk. Single‐cell transcriptomic analysis revealed cell‐type‐specific enrichment, with SWAP70 prevalent in B cells and LTBR in dendritic cells. Bulk RNA ‐seq confirmed the upregulation of SWAP70 , RASGRP1 , and RHOH in RA patients. Conclusion Our integrative multi‐omics framework reveals immune regulatory genes with potential causal roles in RA pathogenesis, highlighting ERAP2 , SWAP70 , LTBR , and other candidates as promising therapeutic targets.