Identification of candidate genes and pathways associated with juvenile idiopathic arthritis by integrative transcriptome-wide association studies and mRNA expression profiles

Abstract

Aim Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood, with genetic susceptibility and pathological processes such as autoimmunity and autoinflammation, but its pathogenesis is unclear. We conducted a transcriptome-wide association study (TWAS) using expression interpolation from a large-scale genome-wide association study (GWAS) dataset to identify genes, biological pathways, and environmental chemicals associated with JIA. Methods We obtained published GWAS data on JIA for TWAS and used mRNA expression profiling to validate the genes identified by TWAS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. A protein–protein interaction (PPI) network was generated, and central genes were obtained using Molecular Complex Detection (MCODE). Finally, chemical gene expression datasets were obtained from the Comparative Toxicogenomics database for chemical genome enrichment analysis. Results TWAS identified 1481 genes associated with JIA, and 154 differentially expressed genes were identified based on mRNA expression profiles. After comparing the results of TWAS and mRNA expression profiles, we obtained eight overlapping genes. GO and KEGG enrichment analyses of the genes identified by TWAS yielded 163 pathways, and PPI network analysis as well as MCODE resolution identified a total of eight clusters. Through chemical gene set enrichment analysis, 287 environmental chemicals associated with JIA were identified. Conclusion By integrating TWAS and mRNA expression profiles, genes, biological pathways, and environmental chemicals associated with JIA were identified. Our findings provide new insights into the pathogenesis of JIA, including candidate genetic and environmental factors contributing to its onset and progression.

Large-scale integrative analysis of juvenile idiopathic arthritis for new insight into its pathogenesis

“…The SNP in a splice site for ERAP2 had a genomewide significant association with JIA [99], and polymorphism in genes encoding ERAP1 and ERAP2 is known to predispose to ERA [118]. While our TWAS genes, MAGI3 and NFATC2IP, were mentioned in previous JIA TWAS studies [81,119,120], we could better understand the genetic contribution of risk genes to JIA pathogenesis by conducting a PWAS together with fine-mapping and TWAS-based pathway enrichment analysis. A proteome-level analysis can provide more relevant biological information, capture alternative splicing, and post-translational modifications about disease mechanisms.…”

Large-scale Integrative Analysis of Juvenile Idiopathic Arthritis for New Insight into Its Pathogenesis

“…ERAP2 reportedly has crucial roles in immunomodulating immune responses 116 . While our TWAS genes, MAGI3 and NFATC2IP, were mentioned in previous JIA TWAS studies 81,117,118 , we could better understand the genetic contribution of risk genes to JIA pathogenesis by conducting a PWAS together with finemapping and TWAS-based pathway enrichment analysis. A proteome-level analysis can provide more relevant biological information, capture alternative splicing, and post-translational modifications about disease mechanisms.…”