A Cross-Tissue Transcriptome Association Study Revealed Novel Susceptibility Genes for Chronic Obstructive Pulmonary Disease.

Abstract

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, with its pathogenesis remaining elusive. Genetic factors are recognized as crucial factors in the pathogenesis of COPD. METHODS: This study employed transcriptome-wide association studies (TWAS) and single cell transcriptome analysis to identify predisposition genes and potential mechanisms for COPD. Cross-tissue TWAS analysis was performed using the FinnGen R10 database and sCCA weights built from the GTEx v8. Single-tissue and single-cell validations were conducted using a FUSION method based on functional summaries. SMR and colocalization analysis were carried out. C57BL/6 mice and Beas-2b cells were exposed to smoke to simulate COPD inflammation and verify the function of the genes. The regulatory effect of genes was verified by overexpression of plasmid and siRNA. Eventually, single-cell transcriptomics was conducted to investigate the expression of susceptibility genes in lung tissue cells, while GeneMANIA analysis enhanced our insights into the functional significance of these genes. RESULTS: A total of 125 susceptibility genes associated with COPD were identified by cross-tissue TWAS analysis. Single-tissue and single-cell TWAS, along with MAGMA validation, revealed two novel susceptibility genes, DNAJA4 and IREB2. SMR and colocalization analysis further confirmed these findings. Both mouse and cell experiments can prove that the occurrence of COPD is related to two genes. Both genes exhibit specific cell type enrichment in the lung tissue of COPD patients. The GeneMANIA analysis revealed that DNAJA4 and IREB2 potentially influence COPD risk by regulating protein folding and modification and metabolic processes, respectively. CONCLUSION: We identified two novel susceptibility genes (DNAJA4 and IREB2) that are causally associated with COPD. These results provide a new perspective on the genetics of COPD.