摘要
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 colocalization 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 colocalization analysis to confirm that the expression quantitative trait loci and RA share causal genetic variants.Furthermore,we implemented a phenomewide scan to identify other clinical phenotypes associated with significant causal genes.Results:At a Bonferroni significance level of p<2.70×10^(−6),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.
基金
Basic and Applied Basic Research Foundation of Guangdong Province,Grant/Award Numbers:2023A1515011768,2020A1515010221,2021A1515010535
National Natural Science Foundation of China,Grant/Award Numbers:82271818,81871275,82071831,82001714,81671591,81501389,81373182。
