幼年特发性关节炎 (JIA) 是一种自身免疫性关节疾病，经常与其他复杂表型同时发生，包括癌症和其他自身免疫性疾病。尽管通过全基因组关联研究 (GWAS) 鉴定了许多风险变异，但受影响的基因、它们与 JIA 发病机制的联系以及它们在相关性状发展中的作用仍不清楚。本研究旨在通过阐明 JIA 发病机制背后的基因调控机制并探索其在相关性状出现中的潜在作用来解决这些空白。进行了两个样本孟德尔随机化 (MR) 分析，以确定与 JIA 因果关系相关的血液表达基因贾。随后使用精心设计的蛋白质相互作用网络来识别调节 JIA 因果基因及其蛋白质相互作用伙伴的表达的单核苷酸多态性集（即空间 eQTL SNP）。这些 SNP 与 GWAS 目录进行交叉引用，以确定与 JIA 相关的统计丰富性状。两个样本的 MR 分析确定了 52 个基因，这些基因在血液中的表达变化被认为与 JIA 相关。这些基因（例如 HLA、LTA、LTB、IL6ST）参与一系列免疫相关途径（例如抗原呈递、细胞因子信号传导），并展示不同免疫细胞类型之间的细胞类型特异性调节模式（例如 CD4 中的 PPP1R11） T 细胞）。调节 JIA 因果基因及其相互作用伙伴的空间 eQTL 在统计上富集了与 95 个其他性状（包括已知和新的 JIA 相关性状）相关的 GWAS SNP。这项综合分析确定了一些基因，这些基因的失调可以解释 JIA 与相关特征之间的联系，例如自身免疫/炎症性疾病（6p22.1 位点的基因）、霍奇金淋巴瘤（6p21.3 位点的基因 [FKBPL、PBX2、AGER]）和慢性淋巴细胞白血病 (BAK1)。我们的方法在了解 JIA 的遗传结构和相关特征方面取得了重大进展。结果表明，幼年特发性关节炎患者的相关特征负担可能有所不同，这受到不同特征群的组合遗传风险的影响。未来对已识别连接的实验验证可以为精细的患者分层、新生物标志物的发现和共享治疗靶点铺平道路。版权所有 © 2024 Pudjihartono、Ho 和 O’Sullivan。

Juvenile idiopathic arthritis (JIA) is an autoimmune joint disease that frequently co-occurs with other complex phenotypes, including cancers and other autoimmune diseases. Despite the identification of numerous risk variants through genome-wide association studies (GWAS), the affected genes, their connection to JIA pathogenesis, and their role in the development of associated traits remain unclear. This study aims to address these gaps by elucidating the gene-regulatory mechanisms underlying JIA pathogenesis and exploring its potential role in the emergence of associated traits.A two-sample Mendelian Randomization (MR) analysis was conducted to identify blood-expressed genes causally linked to JIA. A curated protein interaction network was subsequently used to identify sets of single-nucleotide polymorphisms (i.e., spatial eQTL SNPs) that regulate the expression of JIA causal genes and their protein interaction partners. These SNPs were cross-referenced against the GWAS catalog to identify statistically enriched traits associated with JIA.The two-sample MR analysis identified 52 genes whose expression changes in the blood are putatively causal for JIA. These genes (e.g., HLA, LTA, LTB, IL6ST) participate in a range of immune-related pathways (e.g., antigen presentation, cytokine signalling) and demonstrate cell type-specific regulatory patterns across different immune cell types (e.g., PPP1R11 in CD4+ T cells). The spatial eQTLs that regulate JIA causal genes and their interaction partners were statistically enriched for GWAS SNPs linked with 95 other traits, including both known and novel JIA-associated traits. This integrative analysis identified genes whose dysregulation may explain the links between JIA and associated traits, such as autoimmune/inflammatory diseases (genes at 6p22.1 locus), Hodgkin lymphoma (genes at 6p21.3 [FKBPL, PBX2, AGER]), and chronic lymphocytic leukemia (BAK1).Our approach provides a significant advance in understanding the genetic architecture of JIA and associated traits. The results suggest that the burden of associated traits may differ among JIA patients, influenced by their combined genetic risk across different clusters of traits. Future experimental validation of the identified connections could pave the way for refined patient stratification, the discovery of new biomarkers, and shared therapeutic targets.Copyright © 2024 Pudjihartono, Ho and O’Sullivan.