Genetic Association of Juvenile Idiopathic Arthritis With Adult Rheumatic Disease

Abstract

Importance: Patients with juvenile idiopathic arthritis (JIA) may develop adult rheumatic diseases later in life, and prolonged or recurrent disease activity is often associated with substantial disability; therefore, it is important to identify patients with JIA at high risk of developing adult rheumatic diseases and provide specialized attention and preventive care to them.

Objective: To elucidate the full extent of the genetic association of JIA with adult rheumatic diseases, to improve treatment strategies and patient outcomes for patients at high risk of developing long-term rheumatic diseases.

Design, setting, and participants: In this genetic association study of 4 disease genome-wide association study (GWAS) cohorts from 2013 to 2024 (JIA, rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], and systemic sclerosis [SSc]), patients in the JIA cohort were recruited from the US, Australia, and Norway (with a UK cohort included in the meta-analyzed cohort), while patients in the other 3 cohorts were recruited from US and Western European countries. All analyses were conducted between September 2023 and April 2024.

Exposures: Genetic associations.

Main outcomes and measures: Genetic correlations and shared genomic loci between JIA and adult rheumatic diseases. Genetic correlation analyses and cross-trait meta-analysis were conducted on the JIA cohort and the summary statistics of the GWASs from adult rheumatic diseases (RA, SLE, and SSc). Mendelian randomization analyses were also conducted.

Results: This study included 33 207 patients across the 4 cohorts, with 4550 patients in the meta-analyzed JIA cohort (JIA cohort: 1485 patients with arthritis onset before 16 years; 1017 female [68.5%]; 10 352 controls; UK cohort: 3305 patients with JIA; 9196 controls), 143 61 patients in the RA cohort, 5201 patients in the SLE cohort; and 9095 patients in the SSc cohort. After the GWAS result of the JIA cohort was meta-analyzed with the UK JIA cohort, there was a total of 4550 JIA cases and 18 446 controls. The analysis revealed a significant global correlation between JIA and adult rheumatic diseases, with 84 regions harboring signals associated with multiple diseases. Cross-trait analyses uncovered novel disease loci and 20 loci associated with JIA and adult diseases. Mendelian randomization analysis revealed the significant association of 11 proteins with rheumatic disorders. Both shared, organ-specific, and disease-specific critical cell types were highlighted.

Conclusions and relevance: In this genetic association study, there was significant genetic overlap between JIA and adult rheumatic diseases. These findings may help to refine JIA classification, risk stratification, and therapeutic strategy of repurposing adult disease drugs for pediatric patients with similar mechanisms.

Figure 1.. Overview of the Study Design and Analyses

ASSET indicates association analysis based on subsets; COLOC, colocalization; DGIdb, Drug-Gene Interaction database; GRS, genetic risk score; GWAS, genome-wide association study; JIA, juvenile idiopathic arthritis; LDSC, linkage disequilibrium score regression; LOGODetect, local genetic correlation detector; pQTL, protein quantitative trait loci; RA, rheumatoid arthritis; scDRS, single-cell disease-relevance score; sc-RNA-seq, single-cell RNA sequencing; SLE, systemic lupus erythematosus; SMR, summary-databased mendelian randomization; SSc, systemic sclerosis; TWAS, transcriptome-wide association study; TWMR, 2-sample mendelian randomization.

Figure 2.. Circos Plot Showing the Shared Genetic Regions Between Pairs of the 4 Rheumatic Diseases

Each colored track presents 1 pairwise disease. The labeled genes passed nominal statistical significance (P < .05) conducted by the Genome-Wide Complex Trait Analysis software package for colocalized genetic regions. JIA indicates juvenile idiopathic arthritis; Mb, megabase; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Figure 3.. Mendelian Randomization Analyses With Cis-Protein Quantitative Trait Locus Data for Significantly Associated Proteins

The circles represent the results for proteins on 4 autoimmune rheumatic diseases. Labeled proteins reached the significance threshold after Bonferroni correction. Blue indicates the proteins with a negative association with diseases, while orange indicates positive associations.

Figure 4.. Associations of Cell Types in Blood With Genetic Risk of Autoimmune Rheumatic Disorders

The heatmap depicts associations of cell type with disease for each of the 4 diseases. The darkness of heatmap colors denotes the proportion of significantly associated cells for each disease. Squares represent significant associations of cell type with disease with multiple testing adjustment (false discovery rate [FDR] < .05). aβ indicates amyloid-β; JIA juvenile idiopathic arthritis; NK, natural killer; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.