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.