Transcriptome-wide Association Studies Integrating Four Levels Identify Novel Targets for Idiopathic Pulmonary Fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a kind of interstitial lung disease with a poor prognosis. Even though genome-wide association studies (GWAS) have identified numerous loci linked to IPF risk, the underlying causal genes and biological processes are still mostly unknown.

Methods: The IPF GWAS summary data included 4,125 cases, 20,464 controls from five cohorts. The weight file and related files for transcriptome association studies (TWAS) of plasma protein, multi-tissues, cross-tissue, and single-cell were obtained from Zhang's study, Mancuso lab, GTExV8 database, and Thompson's study, respectively. We conducted TWAS employing functional Summary-based Imputation (FUSION) from four levels, which were plasma protein, multiple tissues, cross-tissue, and single cell. Conditional and joint (COJO) analysis and multi-marker analysis of genomic annotation (MAGMA) analysis were used to validate the above results. Summary-data-based Mendelian randomization (SMR) and Bayesian co-localization analysis were utilized to explain the causal association between selected genes and the risk of IPF.

Results: A total of 12, 361, 1187, and 72 genes were calculated from the four dimensions of TWAS. TOLLIP, GCHFR, ZNF318 TALDO1, CD151, and AP4M1 were selected by intersecting the results of the four sets of genes. GCHFR, TALDO1, CD151, and AP4M1 were verified by COJO analysis and MAGMA analysis. SMR and colocalization analyses identified GCHFR as the most significant gene for IPF.

Discussion: We have applied the TWAS approach to identify novel therapeutic targets for IPF in multiple dimensions. Further biological testing will be required in future studies to validate our findings.

Conclusion: In summary, we carried out an extensive TWAS that integrated four dimensions: plasma protein, multiple tissues, cross-tissue, and single cell. GCHFR was identified as the most significant gene for IPF in this study.