Gong Weiming, Guo Ping, Liu Lu, Guan Qingbo, Yuan Zhongshang
Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Front Genet. 2020 Dec 10;11:604324. doi: 10.3389/fgene.2020.604324. eCollection 2020.
Idiopathic pulmonary fibrosis (IPF) is a type of scarring lung disease characterized by a chronic, progressive, and irreversible decline in lung function. The genetic basis of IPF remains elusive. A transcriptome-wide association study (TWAS) of IPF was performed by FUSION using gene expression weights of three tissues combined with a large-scale genome-wide association study (GWAS) dataset, totally involving 2,668 IPF cases and 8,591 controls. Significant genes identified by TWAS were then subjected to gene ontology (GO) and pathway enrichment analysis. The overlapped GO terms and pathways between enrichment analysis of TWAS significant genes and differentially expressed genes (DEGs) from the genome-wide mRNA expression profiling of IPF were also identified. For TWAS significant genes, protein-protein interaction (PPI) network and clustering modules analyses were further conducted using STRING and Cytoscape. Overall, TWAS identified a group of candidate genes for IPF under the Bonferroni corrected value threshold (0.05/14929 = 3.35 × 10), such as ( = 1.35 × 10 for lung tissue), ( = 1.09 × 10 for lung tissue), and ( = 1.41 × 10 for whole blood). Pathway enrichment analysis identified multiple candidate pathways, such as herpes simplex infection ( value = 7.93 × 10) and antigen processing and presentation ( value = 6.55 × 10). 38 common GO terms and 8 KEGG pathways shared by enrichment analysis of TWAS significant genes and DEGs were identified. In the PPI network, 14 genes (, , , , , , , , , , , , , and ) were simultaneously detected by hub gene and module analysis. In conclusion, through integrative analysis of TWAS and mRNA expression profiles, we identified multiple novel candidate genes, GO terms and pathways for IPF, which contributes to the understanding of the genetic mechanism of IPF.
特发性肺纤维化（IPF）是一种瘢痕性肺疾病，其特征是肺功能呈慢性、进行性和不可逆下降。IPF的遗传基础仍然不明。FUSION利用三种组织的基因表达权重结合大规模全基因组关联研究（GWAS）数据集进行了IPF的全转录组关联研究（TWAS），共纳入2668例IPF病例和8591例对照。然后对TWAS鉴定出的显著基因进行基因本体（GO）和通路富集分析。还确定了TWAS显著基因富集分析与IPF全基因组mRNA表达谱中的差异表达基因（DEG）之间重叠的GO术语和通路。对于TWAS显著基因，使用STRING和Cytoscape进一步进行蛋白质-蛋白质相互作用（PPI）网络和聚类模块分析。总体而言，在Bonferroni校正值阈值（0.05/14929 = 3.35×10）下，TWAS鉴定出一组IPF候选基因，如（肺组织中 = 1.35×10）、（肺组织中 = 1.09×10）和（全血中 = 1.41×10）。通路富集分析确定了多个候选通路，如单纯疱疹感染（值 = 7.93×10）和抗原加工与呈递（值 = 6.55×10）。确定了TWAS显著基因和DEG富集分析共有的38个常见GO术语和8条KEGG通路。在PPI网络中，通过枢纽基因和模块分析同时检测到14个基因（、、、、、、、、、、、、和）。总之，通过对TWAS和mRNA表达谱的综合分析，我们鉴定出多个IPF新的候选基因、GO术语和通路，这有助于理解IPF的遗传机制。
