Primary biliary cholangitis(PBC)is an autoimmune disease involving dysregulation of a broad array of homeostatic and metabolic processes.Although considerable single-nucleotide polymorphisms have been unveiled,a large fraction of risk factors remains enigmatic.Candidate genes with rare mutations that tend to confer more deleterious effects need to be identified.To help pinpoint cellular and developmental mech-anisms beyond common noncoding variants,we integrate whole exome sequencing with integrative network analysis to investigate genes harboring de novo mutations.Prominent convergence has been revealed on a network of disease-specific co-expression comprised of 55 genes associated with homeo-stasis and metabolism.The transcription factor gene MEF2D and the DNA repair gene PARP2 are high-lighted as hub genes and identified to be up-and down-regulated,respectively,in peripheral blood data set.Enrichment analysis demonstrates that altered expression of MEF2D and PARP2 may trigger a series of molecular and cellular processes with pivotal roles in PBC pathophysiology.Our study identifies genes with de novo mutations in PBC and suggests that a subset of genes in homeostasis and metabolism tend to act in synergy through converging on co-expression network,providing novel insights into the etiology of PBC and expanding the pool of molecular candidates for discovering clinically actionable biomarkers.