Objectives: Juvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear. We conducted a comprehensive integrative analysis to gain new insights into the etiology of JIA. Methods: To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand genetic architecture JIA, we systematically analyzed single nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Finally, we performed HLA typing using multi-ancestry RNA sequencing data and analyzed the T cell receptor (TCR) repertoire at a single-cell level to investigate the associations between immunity and JIA risk. Results: We have identified 19 TWAS genes and two PWAS proteins that are associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions, and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13+BHLHE40+ TH cells which are significantly associated with JIA risks. Conclusions: Our findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA

The authors have declared no competing interest.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2021R1A2C1008804). Also, this work was supported by Korea Environment Industry & Technology Institute (KEITI) through Core Technology Development Project for Environmental Diseases Prevention and Management Program (or Project), funded by Korea Ministry of Environment (MOE) (2022003310014 (NTIS 1485018840)).

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