GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
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DOI：
10.1038/s41467-019-12760-y
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发表时间：
2019-10-31
影响因子：
16.6
通讯作者：
Martin, Javier
中科院分区：
文献类型：
--
作者：
Lopez-Isac, Elena;Acosta-Herrera, Marialbert;Martin, Javier
系统性硬化症（SSc）是一种自身免疫性疾病，是风湿性疾病中死亡率最高的疾病之一。我们对 26,679 名个体进行了一项大型全基因组关联研究 (GWAS)，并对之前的 GWAS 进行了荟萃分析，并确定了 27 个独立的全基因组关联信号，包括 13 个新的风险位点。这些新的关联使迄今为止 SSc 报道的全基因组命中数几乎翻了一番。我们在 12 个基因座中定义了少于 5 个可能因果变异的 95% 可信集。此外，我们还识别了特定的 SSc 亚型相关信号。高优先级变体的功能分析显示了 SSc 信号的潜在功能，并通过 HiChIP 鉴定了 43 个稳健的靶基因。我们的结果指出了可能涉及血管病变和纤维化（SSc 的两个主要标志）的分子途径，并强调了该疾病的关键细胞类型谱。这项工作支持更好地理解 SSc 的遗传基础，并为未来的功能实验提供方向。
Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.