Integrative Analysis of Transcriptome-Wide Association Study and mRNA Expression Profiles Identifies Candidate Genes Associated With Idiopathic Pulmonary Fibrosis.

Weiming Gong,Ping Guo,Qingbo Guan,Lu Liu,Zhongshang Yuan

doi:10.3389/fgene.2020.604324

Abstract

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 P value threshold (0.05/14929 = 3.35 × 10–6), such as DSP (PTWAS = 1.35 × 10–29 for lung tissue), MUC5B (PTWAS = 1.09 × 10–28 for lung tissue), and TOLLIP (PTWAS = 1.41 × 10–15 for whole blood). Pathway enrichment analysis identified multiple candidate pathways, such as herpes simplex infection (P value = 7.93 × 10–5) and antigen processing and presentation (P value = 6.55 × 10–5). 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 (DYNLL1, DYNC1LI1, DYNLL2, HLA-DRB5, HLA-DPB1, HLA-DQB2, HLA-DQA2, HLA-DQB1, HLA-DRB1, POLR2L, CENPP, CENPK, NUP133, and NUP107) 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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by the formation of scar tissue and a progressive, and irreversible decline in lung function (Raghu et al, 2011; Lederer and Martinez, 2018), with a median survival time from diagnosis of 2–4 years (Ley et al, 2011)
Genome-wide association studies (GWAS) on IPF (Mushiroda et al, 2008; Fingerlin et al, 2013, 2016; Noth et al, 2013; Allen et al, 2017, 2020) have identified common genetic variants related to IPF, highlighting the significance of several IPF susceptibility factors, such as telomere maintenance, host defense, cell-cell adhesion
For Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the genes identified by transcriptome-wide association study (TWAS), Metascape detected 30 candidate pathways for IPF under P value < 0.01 (Figure 3 and Supplementary Table S3), such as Staphylococcus aureus infection (PTWAS = 3.69 × 10−7), allograft rejection (PTWAS = 4.45 × 10−6), asthma (PTWAS = 7.65 × 10−6), type I diabetes mellitus (PTWAS = 1.32 × 10−5), inflammatory bowel disease (IBD) (PTWAS = 7.37 × 10−5), and herpes simplex infection (PTWAS = 7.93 × 10−5)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by the formation of scar tissue and a progressive, and irreversible decline in lung function (Raghu et al, 2011; Lederer and Martinez, 2018), with a median survival time from diagnosis of 2–4 years (Ley et al, 2011). IPF has been confirmed to be related to varieties of environmental and genetic factors. Genome-wide association studies (GWAS) on IPF (Mushiroda et al, 2008; Fingerlin et al, 2013, 2016; Noth et al, 2013; Allen et al, 2017, 2020) have identified common genetic variants related to IPF, highlighting the significance of several IPF susceptibility factors, such as telomere maintenance, host defense, cell-cell adhesion. Rare genetic variants regarding surfactant dysfunction and telomere biology have been identified in studies of familial pulmonary fibrosis (Nogee et al, 2001; Armanios et al, 2007; Cogan et al, 2015; Stuart et al, 2015)

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