Juvenile Idiopathic Arthritis (JIA) is the most common type of arthritis among children, encompassing a highly heterogeneous group of immune-mediated joint disorders, being classified into seven subtypes based on clinical presentation. To systematically understand the distinct and shared genetic underpinnings of JIA subtypes, we conducted a heterogeneity-sensitive GWAS encompassing a total of 1245 JIA cases classified into 7 subtypes and 9250 controls. In addition to the MHC locus, we uncovered 16 genome-wide significant loci, among which 15 were shared between at least two JIA subtypes, including 11 novel loci. Functional annotation indicates that candidate genes at these loci are expressed in diverse immune cell types. Further, based on the association results, the 7 JIA subtypes were classified into two groups, reflecting their autoimmune vs autoinflammatory nature. Our results suggest a common genetic mechanism underlying these subtypes in spite of their different clinical disease phenotypes, and that there may be drug repositioning opportunities for rare JIA subtypes.

中文翻译：

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幼年特发性关节炎的综合遗传学分析确定了新的基因位点。

幼年特发性关节炎（JIA）是儿童中最常见的关节炎类型，包括高度异质的一组免疫介导的关节疾病，根据临床表现可分为7种亚型。为了系统地了解JIA亚型的独特和共有的遗传基础，我们进行了异质性敏感的GWAS，涵盖了总共1245例JIA病例，分为7个亚型和9250个对照。除了MHC基因座，我们还发现了16个全基因组显着基因座，其中15个在至少两个JIA亚型之间共享，其中包括11个新基因座。功能注释表明这些基因座的候选基因在多种免疫细胞类型中表达。此外，根据关联结果，将7种JIA亚型分为两组，反映出自身免疫性与自身炎症性。我们的结果表明，尽管这些亚型具有不同的临床疾病表型，但它们仍是常见的遗传机制，而且对于罕见的JIA亚型可能存在重新定位药物的机会。