A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes for Juvenile Idiopathic Arthritis in Asia and Europe

Abstract

Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, and its pathogenesis is still unclear. Genome-wide association studies (GWASs) of JIA have identified hundreds of risk factors, but few of them implicated specific biological mechanisms.

Methods: A cross-tissue transcriptome-wide association study (TWAS) was performed with the functional summary-based imputation software (FUSION) tool based on GWAS summary datasets (898 JIA patients and 346,102 controls from BioBank Japan (BBJ)/FinnGen). The gene expression reference weights of skeletal muscle and the whole blood were obtained from the Genotype-Tissue Expression (GTExv8) project. JIA-related genes identified by TWAS findings genes were further compared with the differentially expressed genes (DEGs) identified by the mRNA expression profile of JIA from the Gene Expression Omnibus (GEO) database (accession number: GSE1402). Last, candidate genes were analyzed using functional enrichment and annotation analysis by Metascape to examine JIA-related gene sets.

Results: The TWAS identified 535 significant genes with P < 0.05 and contains 350 for Asian and 195 for European (including 10 genes both expressed in Asian and European), such as CDC16 (P = 1.72E-03) and PSMD5-AS1 (P = 3.65E-02). Eight overlapping genes were identified based on TWAS results and DEGs of JIA patients, such as SIRPB1 (P_TWAS = 4.21E-03, P_DEG = 1.50E-04) and FRAT2 (P_TWAS = 2.82E-02, P_DEG = 1.43E-02). Pathway enrichment analysis of TWAS identified 183 pathways such as cytokine signaling in the immune system and cell adhesion molecules. By integrating the results of DEGs pathway and process enrichment analyses, 19 terms were identified such as positive regulation of T-cell activation.

Conclusion: By conducting two populations TWAS, we identified a group of JIA-associated genes and pathways, which may provide novel clues to uncover the pathogenesis of JIA.

Keywords: gene ontology; juvenile idiopathic arthritis; mRNA expression profiles; pathway enrichment; transcriptome-wide association study.

Figure 1

Manhattan plot showing transcriptome-wide association study (TWAS)–identified genes. Manhattan plot showing TWAS-identified genes and significantly expressed genes associated with juvenile idiopathic arthritis (JIA; annotated points) for Asian (A) and European (B) populations. Each point represents a single gene, and the physical position (chromosome localization) is plotted on the x-axis, whereas the −log₁₀ (P-value) of the association between gene and JIA is plotted on the y-axis. TWAS, transcriptome-wide association study; JIA, juvenile idiopathic arthritis.

Figure 2

Venn diagram reveals the overlap of transcriptome-wide association study (TWAS)-significant genes in different populations and tissues. TWAS: transcriptome-wide association study; BBJ, BioBank Japan; FIN, FinnGen; SM, skeletal muscle; WB, whole blood.

Figure 3

The volcano plot of mRNA expression profiles for juvenile idiopathic arthritis (JIA). The results of mRNA expression profiles were output to the volcano map. Genes were marked in red point as differentially expressed when the following two conditions were met: P < 0.05 by the moderated t statistic and |logFC| > 1. JIA, juvenile idiopathic arthritis; logFC, log fold change.

Figure 4

The top overrepresented Gene Ontology (GO) terms and related genes. Sankey plot showed the relationship between the genes and overrepresented GO terms. The dot plot showed the ratio between the genes identified involved in GO terms and the total number of genes included in each GO terms (FDR P ≤ 0.05). GO, Gene Ontology.