单细胞测序分析鉴定出受遗传调控的 ORMDL3 胆管细胞对原发性胆汁性胆管炎具有更高的代谢影响。

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

机构信息

Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.

School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150080, China.

出版信息

J Nanobiotechnology. 2021 Dec 6;19(1):406. doi: 10.1186/s12951-021-01154-2.

DOI:10.1186/s12951-021-01154-2

PMID:34872583

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8647381/

Abstract

BACKGROUND

Primary 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.

RESULTS

We 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). 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.

CONCLUSIONS

To 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.

摘要

背景

原发性胆汁性胆管炎（PBC）是一种经典的自身免疫性疾病，高度受遗传决定因素影响。许多全基因组关联研究（GWAS）已经报道，许多遗传位点与 PBC 易感性显著相关。然而，遗传决定因素对 PBC 患者的肝细胞及其免疫微环境的影响尚不清楚。

结果

我们构建了一个强大的计算框架，将 GWAS 汇总统计数据与 scRNA-seq 数据相结合，以揭示与 PBC 相关的遗传调控的肝细胞亚群。基于我们的多组学综合分析，包括 ORMDL3、GSNK2B 和 DDAH2 在内的 29 个风险基因与 PBC 易感性显著相关。通过将 GWAS 汇总统计数据与 scRNA-seq 数据相结合，我们发现胆管细胞表现出明显的 PBC 相关遗传关联信号富集（置换 P < 0.05）。风险基因 ORMDL3 在胆管细胞中的表达比例明显高于其他肝细胞（22.38%）。ORMDL3 胆管细胞的代谢活性评分明显高于 ORMDL3 胆管细胞（P = 1.38×10）。与 ORMDL3 胆管细胞相比，ORMDL3 胆管细胞中有 77 个基因表达存在显著差异（FDR < 0.05），这些显著差异基因与自身免疫性疾病相关的功能术语或途径有关。ORMDL3 胆管细胞与巨噬细胞和单核细胞的通讯相对较高。与 ORMDL3 胆管细胞相比，VEGF 信号通路是 ORMDL3 胆管细胞与其他细胞群体相互作用的特异性通路。