Genetically supported causal genes for rheumatoid arthritis: Mendelian randomization and co-localization analyses

Background: Rheumatoid arthritis (RA) is a globally prevalent condition that has a significant impact on morbidity and mortality rates. As a result, there is growing interest in understanding its pathogenetic mechanisms, particularly genetic susceptibility. To explore the potential genes that may cause RA, we conducted a comprehensive Mendelian randomization analysis and co-localization based on data from large sample size genome-wide association studies. Methods: We used two transcriptome datasets to identify expression quantitative trait loci as the exposure and employed genome-wide association studies data from the FinnGen study as the outcome. We then performed co-localization analysis to confirm that the expression quantitative trait loci and RA share causal genetic variants. Furthermore, we implemented a phenome-wide scan to identify other clinical phenotypes associated with significant causal genes. Results: At a Bonferroni significance level of p < 2.70 × 10, the Mendelian randomization analysis revealed that 20 genes increased the risk of RA, while 16 genes showed a marginally protective effect. Co-localization analyses indicated that AP4B1, GGA2, KEAP1, PTPN22, REG4, and TRAV38-2DV8 were associated with the risk of RA. The phenome-wide scan demonstrated shared genetic determinants between RA and other immune-mediated disorders, including autoimmune thyroid disease, diabetes mellitus, cardiovascular disorders, inflammatory bowel disease, and malignant tumors. Conclusions: Our study identified six risk genes (AP4B1, GGA2, KEAP1, PTPN22, REG4, and TRAV38-2DV8) that may have a causal role in RA. These findings provide novel therapeutic targets for the treatment of RA. Further exploration is required to elucidate the underlying biological mechanisms.