Mapping of <i>de novo</i> mutations in primary biliary cholangitis to a disease-specific co-expression network underlying homeostasis and metabolism

Lu Wang; Jinchen Li; Chan Wang; Ruqi Tang; Jialong Liang; Yuhua Gong; Yaping Dai; Ningling Ding; Jian Wu; Na Dai; Lei Liu; Yi Zhao; Youlin Shao; Weifeng Zhao; Peng Jiang; Xingjuan Shi; Weichang Chen; Ye Tian; Xiangdong Liu; Xiong Ma; Zhongsheng Sun

doi:10.1016/j.jgg.2021.07.019

Volume 49 Issue 2

Mar. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(2): 145-154

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Mapping of de novo mutations in primary biliary cholangitis to a disease-specific co-expression network underlying homeostasis and metabolism

doi: 10.1016/j.jgg.2021.07.019

a Key Laboratory of Developmental Genes and Human Diseases, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, Jiangsu 210096, China;
b Beijing Institutes of Life Science, Chinese Academy of Sciences, No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China;
c Department of Gastroenterology and Hepatology, Shanghai Institute of Digestive Diseases, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, 145 Shandong Middle Road, Shanghai 200001, China;
d Department of Laboratory Medicine, The Third People's Hospital of Zhenjiang, 300 Daijiamen, Zhenjiang, Jiangsu 212021, China;
e Department of Laboratory Medicine, The Fifth People's Hospital of Wuxi, 1215 Guangrui Road, Wuxi, Jiangsu 214000, China;
f Department of Hepatology, The Fifth People's Hospital of Suzhou, Soochow University, 10 Guangqian Road, Suzhou, Jiangsu 215131, China;
g Department of Rheumatology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu 215006, China;
h Department of Gastroenterology, Jiangsu University Affiliated Kunshan Hospital, 91 Qianjin West Road, Kunshan, Jiangsu 215300, China;
i Department of Gastroenterology, Yixing People's Hospital, 75 Tongzhenguan Road, Yixin, Jiangsu 214200, China;
j Department of Gastrointestinal Endoscopy, Eastern Hepatobiliary Surgery Hospital, 700 Moyu North Road, Shanghai 201800, China;
k Department of Hepatology, The Third People's Hospital of Changzhou, 300 Lanling North Road, Changzhou, Jiangsu 213001, China;
l Department of Infectious Diseases, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu 215006, China;
m Department of Gastroenterology, First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, Jiangsu 215006, China;
n Department of Radiology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu 215004, China;
o Institute of Genomic Medicine, Wenzhou Medical University, University Town, Chashan, Wenzhou, Zhejiang 325035, China

Funds:

and 81570469 to R.Q.T.), by grants from Jiangsu provincial research fund (BE2017713 to X.D.L and BL2018657 to Y.T.), and a grant from National Key R&

We are grateful to all the subjects for donating DNA samples. This work was supported in part by grants from the National Natural Science Foundation of China (81870397 to X.D.L.

D Program of China (2016YFC0900400).

81620108002, 81771732, 81830016 to X.M

Received Date: 2021-05-08
Accepted Date: 2021-07-26
Rev Recd Date: 2021-07-22
Publish Date: 2021-08-22

Abstract

Abstract

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.
- Primary biliary cholangitis,
- de novo mutations,
- Whole exome sequencing,
- Transcriptional networks,
- Co-expression

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