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 mechanisms 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 homeostasis and metabolism. The transcription factor gene MEF2D and the DNA repair gene PARP2 are highlighted 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.

原发性胆汁性胆管炎 (PBC) 是一种自身免疫性疾病，涉及多种体内平衡和代谢过程的失调。尽管已经揭示了相当多的单核苷酸多态性，但大部分风险因素仍然是神秘的。需要确定具有罕见突变的候选基因，这些突变往往会带来更有害的影响。为了帮助查明常见非编码变体之外的细胞和发育机制，我们将全外显子组测序与综合网络分析相结合，以研究含有从头突变的基因。在由 55 个与体内平衡和新陈代谢相关的基因组成的疾病特异性共表达网络上已经揭示了显着的收敛性。转录因子基因MEF2D和DNA修复基因PARP2被突出显示为中心基因，并在外周血数据集中分别被确定为上调和下调。富集分析表明， MEF2D和PARP2的表达改变可能触发一系列在 PBC 病理生理学中具有关键作用的分子和细胞过程。我们的研究确定了 PBC 中具有从头突变的基因，并表明体内平衡和新陈代谢中的一部分基因倾向于通过在共表达网络上的融合发挥协同作用，为 PBC 的病因学提供了新的见解，并扩大了 PBC 的分子候选池。发现临床上可操作的生物标志物。