Abstract
BACKGROUND: Although genome-wide association studies (GWAS) have identified many genomic regions associated with idiopathic pulmonary fibrosis (IPF), the causal genes and functions remain largely unknown. Many single-cell expression data have become available for IPF, and there is increasing evidence suggesting a shared genetic basis between IPF and other diseases. METHODS: We conducted integrative analyses to improve the power of GWAS. First, we calculated global and local genetic correlations to identify IPF genetically associated traits and local regions. Then, we prioritised candidate genes contributing to local genetic correlation. Second, we performed transcriptome-wide association analysis (TWAS) of 44 tissues to identify candidate genes whose genetically predicted expression level is associated with IPF. To replicate our findings and investigate the regulatory role of the transcription factors (TF) in identified candidate genes, we first conducted the heritability enrichment analysis in TF binding sites. Then, we examined the enrichment of the TF target genes in cell-type-specific differentially expressed genes (DEGs) identified from single-cell expression data of IPF and healthy lung samples. FINDINGS: We identified 12 candidate genes across 13 genomic regions using local genetic correlation, including the POT1 locus (p value=0.00041), which contained variants with protective effects on lung cancer but increasing IPF risk. We identified another 13 novel genes using TWAS. Two TFs, MAFK and SMAD2, showed significant enrichment in both partitioned heritability and cell-type-specific DEGs. INTERPRETATION: Our integrative analysis identified new genes for IPF susceptibility and expanded the understanding of the complex genetic architecture and disease mechanism of IPF.