Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis
Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis
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DOI：
10.1164/rccm.201905-1017oc
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发表时间：
2020-03-01
影响因子：
24.7
通讯作者：
Wain, Louise, V
中科院分区：
文献类型：
--
作者：
Allen, Richard J.;Guillen-Guio, Beatriz;Wain, Louise, V
原理：特发性肺纤维化（IPF）是一种复杂的肺部疾病，其特征是肺部瘢痕形成，据信是由上皮损伤的非典型反应引起的。全基因组关联研究已经报道了涉及多种途径的关联信号，包括宿主防御、端粒维持、信号传导和细胞-细胞粘附。目的：通过识别以前未报道的遗传关联，提高我们对增加IPF易感性的因素的理解。方法：我们对三个独立研究进行了全基因组分析，并对这些结果进行了荟萃分析，以产生迄今为止最大的IPF全基因组关联研究（2,668例IPF病例和8,591例对照）。我们在两个独立的研究（1456例IPF病例和11874例对照）中进行了重复研究，并进行了功能分析（包括统计精细定位、基因表达调查和检测调控区域IPF易感性信号的富集），以确定可能的致病基因。多基因风险评分用于评估未报道的与IPF相关的变异的集体影响。测量和主要结果：我们鉴定并复制了3个与IPF易感性相关的全基因组显著（P < 5 × 10(-8)）信号（与KIF15、MAD1L1和DEPTOR基因表达改变相关），并证实了先前报道的11个位点的相关性。多基因风险评分分析表明，数千种尚未报道的IPF易感性变异的综合作用有助于IPF易感性。结论：DEPTOR表达降低与IPF易感性增加相关的观察结果支持了最近关于mTOR信号在肺纤维化中的重要性的研究。与KIF15和MAD1L1相关的新信号表明，有丝分裂纺锤体组装基因可能在IPF易感性中起作用。
Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated threenewgenome-wide significant (P < 5 x 10(-8)) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.