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. To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk. We have identified 19 TWAS genes and two PWAS proteins 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. 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.

中文翻译：

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幼年特发性关节炎的大规模综合分析，为其发病机制提供新的见解

幼年特发性关节炎 (JIA) 是儿童中最常见的风湿性疾病之一，被归类为自身免疫性疾病 (AID)。尽管遗传对幼年特发性特发性关节炎（JIA）病因的显着影响已被确定，但确切的发病机制仍不清楚。为了优先考虑 JIA 的生物学可解释易感基因和蛋白质，我们进行了转录组范围和蛋白质组范围的关联研究 (TWAS/PWAS)。然后，为了了解 JIA 的遗传结构，我们系统地分析了基于单核苷酸多态性 (SNP) 的遗传力、自然选择的特征和多基因性。接下来，我们利用多种族 RNA 测序数据进行 HLA 分型。此外，我们在单细胞水平上检查了 T 细胞受体 (TCR) 库，以探索免疫与 JIA 风险之间的潜在联系。我们已经确定了 19 个 TWAS 基因和两种与 JIA 风险相关的 PWAS 蛋白。此外，我们观察到 JIA 的遗传力和细胞类型富集分析在 T 淋巴细胞和 HLA 区域富集，并且与其他 AID 相比，JIA 显示出更高的多基因性。在多祖先 HLA 分型中，B*45:01 在非洲 JIA 患者中比在欧洲 JIA 患者中更常见，而 DQA1*01:01、DQA1*03:01 和 DRB1*04:01 在欧洲 JIA 患者中出现频率更高贾氏特发性关节炎患者。利用单细胞免疫库分析，我们鉴定了 JIA 患者中克隆扩增的 T 细胞亚群，包括与 JIA 风险显着相关的 CXCL13+BHLHE40+ TH 细胞。我们的研究结果为 JIA 的发病机制提供了新的线索，并为未来旨在揭示 JIA 分子驱动因素的机制研究奠定了坚实的基础。