Transcriptome-wide Association Studies Integrating Four Levels Identify Novel Targets for Idiopathic Pulmonary Fibrosis.

IF 3.5 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current medicinal chemistry Pub Date : 2025-08-26 DOI:10.2174/0109298673364730250721151447

Jiaxin Shi, Linyou Zhang

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引用次数: 0

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a kind of interstitial lung disease with a poor prognosis. Even though genome-wide association studies (GWAS) have identified numerous loci linked to IPF risk, the underlying causal genes and biological processes are still mostly unknown.

Methods: The IPF GWAS summary data included 4,125 cases, 20,464 controls from five cohorts. The weight file and related files for transcriptome association studies (TWAS) of plasma protein, multi-tissues, cross-tissue, and single-cell were obtained from Zhang's study, Mancuso lab, GTExV8 database, and Thompson's study, respectively. We conducted TWAS employing functional Summary-based Imputation (FUSION) from four levels, which were plasma protein, multiple tissues, cross-tissue, and single cell. Conditional and joint (COJO) analysis and multi-marker analysis of genomic annotation (MAGMA) analysis were used to validate the above results. Summary-data-based Mendelian randomization (SMR) and Bayesian co-localization analysis were utilized to explain the causal association between selected genes and the risk of IPF.

Results: A total of 12, 361, 1187, and 72 genes were calculated from the four dimensions of TWAS. TOLLIP, GCHFR, ZNF318 TALDO1, CD151, and AP4M1 were selected by intersecting the results of the four sets of genes. GCHFR, TALDO1, CD151, and AP4M1 were verified by COJO analysis and MAGMA analysis. SMR and colocalization analyses identified GCHFR as the most significant gene for IPF.

Discussion: We have applied the TWAS approach to identify novel therapeutic targets for IPF in multiple dimensions. Further biological testing will be required in future studies to validate our findings.

Conclusion: In summary, we carried out an extensive TWAS that integrated four dimensions: plasma protein, multiple tissues, cross-tissue, and single cell. GCHFR was identified as the most significant gene for IPF in this study.

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整合四个水平的转录组关联研究确定特发性肺纤维化的新靶点。

特发性肺纤维化（Idiopathic pulmonary fibrosis， IPF）是一种预后较差的肺间质性疾病。尽管全基因组关联研究（GWAS）已经确定了许多与IPF风险相关的位点，但潜在的致病基因和生物学过程仍然大多未知。方法：IPF GWAS汇总数据包括来自5个队列的4,125例病例和20,464名对照。血浆蛋白、多组织、跨组织和单细胞转录组关联研究（TWAS）的权重文件和相关文件分别来自Zhang的研究、Mancuso实验室、GTExV8数据库和Thompson的研究。我们从血浆蛋白、多组织、跨组织和单细胞四个水平采用基于功能汇总的Imputation （FUSION）进行TWAS。采用条件联合分析（COJO）和基因组注释多标记分析（MAGMA）对上述结果进行验证。利用基于汇总数据的孟德尔随机化（SMR）和贝叶斯共定位分析来解释所选基因与IPF风险之间的因果关系。结果：从TWAS的四个维度分别计算出12、361、1187和72个基因。通过交叉四组基因的结果选择TOLLIP、GCHFR、ZNF318、TALDO1、CD151和AP4M1。GCHFR、TALDO1、CD151和AP4M1经COJO分析和MAGMA分析验证。SMR和共定位分析确定GCHFR是IPF最重要的基因。讨论：我们已经应用TWAS方法在多个维度上确定IPF的新治疗靶点。在未来的研究中需要进一步的生物学测试来验证我们的发现。结论：总之，我们开展了一个广泛的TWAS，整合了四个维度：血浆蛋白、多组织、跨组织和单细胞。本研究确定GCHFR是IPF最重要的基因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current medicinal chemistry 医学-生化与分子生物学

CiteScore

8.60

自引率

2.40%

发文量

468

审稿时长

3 months

期刊介绍： Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.