Genetic insights into juvenile idiopathic arthritis derived from deep whole genome sequencing.
Genetic insights into juvenile idiopathic arthritis derived from deep whole genome sequencing.
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DOI：
10.1038/s41598-017-02966-9
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发表时间：
2017-06-01
影响因子：
4.6
通讯作者：
Jarvis JN
中科院分区：
文献类型：
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作者：
Wong L;Jiang K;Chen Y;Jarvis JN
深度全基因组测序（WGS）允许以比基于阵列的方法更精细的分辨率对遗传景观进行全面研究。我们对患有多关节型幼年特发性关节炎（JIA）的儿童进行了深度WGS，使用2个独立队列来确定测序保真度。全基因组SNP密度分析与1000个基因组计划（1KGP）数据相比，确定了18个SNP热点。邻近SNP热点的基因子集在免疫过程中显示出统计学显著的富集。与插入缺失热点相邻的基因在功能上与G蛋白偶联信号通路相关。进一步的分析表明，与1KGP数据相比，具有调控潜力的JIA SNP显着更多。此外，位于连锁不平衡（LD）块内的SNP含有先前确定的JIA相关的SNP表现出更高的调节潜力相比，LD块外的SNP。我们还证明了在B细胞中组蛋白修饰峰和DNA酶超敏位点中新的JIA变体的富集。这项研究极大地扩展了可能导致JIA的遗传变异的数量，并为我们提供了一些线索，以了解可能引发这种疾病的原因。到目前为止，这项研究是WGS对JIA儿童的第一次深入研究，为研究社区提供了有用的遗传资源，特别是在了解JIA病因方面。
Deep whole genome sequencing (WGS) allows for the comprehensive study of genetic landscapes at finer resolution than array based methods. We conducted deep WGS on children with the polyarticular form of juvenile idiopathic arthritis (JIA), using 2 independent cohorts to ascertain the sequencing fidelity. Genome wide SNP density analysis identified 18 SNP hotspots with comparison to the 1000 Genome Projects (1KGP) data. A subset of the genes adjacent to SNP hotspots showed statistically significant enrichment in immunological processes. Genes adjacent to indel hotspots were functionally related to G-protein coupled signaling pathways. Further analyses elucidated significantly more JIA SNPs with regulatory potential compared to 1KGP data. Furthermore, SNPs located within linkage disequibilium (LD) blocks containing previously identified JIA-associated SNPs demonstrated higher regulation potential compared to SNPs outside LD blocks. We also demonstrated enrichment of novel JIA variants in histone modification peaks and DNase hypersensitivity sites in B cells. This study greatly expands the number of genetic variants that may contribute to JIA and give us some clues into what may trigger this disease. To date, this study is the first deep WGS effort on children with JIA and provides useful genetic resources for research communities particularly in understanding JIA etiology.