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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  ( P   TWAS   = 1.35 × 10 –29  for lung tissue),  MUC5B  ( P   TWAS   = 1.09 × 10 –28  for lung tissue), and  TOLLIP  ( P   TWAS   = 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.

frontiers in genetics

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