Single cell sequencing analysis identifies genetics-modulated ORMDL3+ cholangiocytes having higher metabolic effects on primary biliary cholangitis

Journal of Nanobiotechnology

Xiuli Lin¹  Mingqin Lu¹  Bingyu Xiang¹  Huifang Zhang¹  Shanshan Li¹  Yijun Zhou²  Yunlong Ma²  Fei Qiu²  Yukuan Huang²  Jianzhong Su³  Chunyu Deng⁴  Jingjing Li⁵ 

[1] Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China;Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, 325027, Wenzhou, Zhejiang, China;Institute of Biomedical Big Data, School of Ophthalmology and Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, 325027, Wenzhou, Zhejiang, China;Wenzhou Institute, University of Chinese Academy of Sciences, 325011, Wenzhou, Zhejiang, China;School of Life Science and Technology, Harbin Institute of Technology, 150080, Harbin, China;State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China;

关键词: Single cell sequencing analysis;    GWAS;    Risk genes;    PBC;    ORMDL3;    Liver cells;   

DOI  :  10.1186/s12951-021-01154-2

来源: Springer

【 摘 要 】

BackgroundPrimary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear.ResultsWe constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations for PBC. Based on our multi-omics integrative analysis, 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). The ORMDL3+ cholangiocytes have prominently higher metabolism activity score than ORMDL3− cholangiocytes (P = 1.38 × 10–15). Compared with ORMDL3− cholangiocytes, there were 77 significantly differentially expressed genes among ORMDL3+ cholangiocytes (FDR < 0.05), and these significant genes were associated with autoimmune diseases-related functional terms or pathways. The ORMDL3+ cholangiocytes exhibited relatively high communications with macrophage and monocyte. Compared with ORMDL3− cholangiocytes, the VEGF signaling pathway is specific for ORMDL3+ cholangiocytes to interact with other cell populations.ConclusionsTo the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3+ cholangiocytes with higher metabolism activity play important immune-modulatory roles in the etiology of PBC.Graphical Abstract

【 授权许可】

CC BY