Combination of single cell sequencing data and GWAS summary statistics reveals genetically-influenced liver cell types for primary biliary cholangitis

Abstract

Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with primary biliary cholangitis (PBC). However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear. We constructed a powerful computational framework to integrate a large-scale GWAS summary statistics (N = 13,239) with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. We found that 29 genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. Gene-property analysis revealed that four immune cell types including Cst3+ dendritic cell, Chil3+ macrophage, Trbc2+ T cell, and Gzma+ T cell were significantly enriched by PBC-risk genes. By combining GWAS summary statistics with scRNA-seq data, we identified that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals. The ORMDL3 gene showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). Compared with ORMDL3+ cholangiocytes, we identified that ORMDL3- cholangiocytes predispose to play important immune-modulatory roles in the etiology of PBC. To the best of our knowledge, this is the first study to integrate human genetic information with single cell sequencing data for parsing genetics-influenced liver cells and its immune microenvironment for PBC risk.