A splicing-based multitissue association study of joint transcriptomes identified susceptibility genes for osteoarthritis.

IF 5.9 2区医学 Q1 IMMUNOLOGY

Frontiers in Immunology Pub Date : 2025-09-11 eCollection Date: 2025-01-01 DOI:10.3389/fimmu.2025.1590008

Lantao Zhang, Fuxing Zhao, Hengheng Zhang, Xingbang Niu, Youliang Li, Chunxia Zhao, Jianhua Ding, Chaozheng Liu

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引用次数: 0

Abstract

Background: Osteoarthritis (OA) is a common chronic degenerative joint disease worldwide, which seriously affects the quality of life of patients and adds economic burden. Although genome-wide association studies (GWAS) have identified multiple genetic loci associated with OA, the functional mechanisms of these loci remain unclear. Transcriptome association studies (TWAS) combining gene expression and GWAS data have provided new perspectives to explore the genetic basis of OA.

Methods: This study integrated cross-tissue and single-tissue TWAS analyses as well as single-cell sequencing data to identify and validate the key genes associated with OA. Cross- and single-tissue analyses were performed using the UTMOST, FUSION, and MAGMA methods, while single-cell sequencing was applied for the investigation of the expression characteristics, pseudotemporal trajectories, and cell-to-cell communication patterns of the latent transforming growth factor beta binding protein 1 (LTBP1) in different cell subtypes.

Results: This study identified multiple candidate genes associated with OA, among which LTBP1 displayed a significant association in both cross-tissue and single-tissue analyses (FDR < 0.05) and was validated as a key regulator of the transforming growth factor-beta (TGF-β) signaling pathway. Single-cell sequencing revealed that LTBP1 was differentially expressed in different chondrocyte subtypes and was associated with high enrichment of the Notch signaling pathway. Pseudotemporal analysis revealed the dynamic regulatory role of LTBP1 in chondrocyte differentiation.

Conclusion: Intercellular communication analysis revealed that cells with high LTBP1 expression activated diverse signaling pathways such as TGF-β and vascular endothelial growth factor (VEGF), suggesting that it may be involved in the pathogenesis of OA by regulating the formation of the extracellular matrix and the immune response.

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基于剪接的关节转录组多组织关联研究确定了骨关节炎的易感基因。

背景：骨关节炎（Osteoarthritis， OA）是世界范围内常见的慢性退行性关节疾病，严重影响患者的生活质量，增加了患者的经济负担。尽管全基因组关联研究（GWAS）已经确定了多个与OA相关的遗传位点，但这些位点的功能机制尚不清楚。结合基因表达和GWAS数据的转录组关联研究（Transcriptome association studies， TWAS）为探索OA的遗传基础提供了新的视角。方法：本研究结合跨组织和单组织TWAS分析以及单细胞测序数据，鉴定和验证OA相关的关键基因。使用maximum、FUSION和MAGMA方法进行跨组织和单组织分析，而单细胞测序用于研究潜伏转化生长因子β结合蛋白1 （LTBP1）在不同细胞亚型中的表达特征、伪时间轨迹和细胞间通信模式。结果：本研究发现了多个与OA相关的候选基因，其中LTBP1在跨组织和单组织分析中均表现出显著的相关性（FDR < 0.05），并被证实是转化生长因子-β (TGF-β)信号通路的关键调控因子。单细胞测序显示，LTBP1在不同软骨细胞亚型中存在差异表达，并与Notch信号通路的高富集有关。伪时间分析揭示了LTBP1在软骨细胞分化中的动态调节作用。结论：细胞间通讯分析显示，LTBP1高表达的细胞激活了TGF-β、血管内皮生长因子（VEGF）等多种信号通路，提示其可能通过调节细胞外基质的形成和免疫应答参与OA发病。

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

Frontiers in Immunology IMMUNOLOGY-

CiteScore

9.80

自引率

11.00%

发文量

7153

审稿时长

14 weeks

期刊介绍： Frontiers in Immunology is a leading journal in its field, publishing rigorously peer-reviewed research across basic, translational and clinical immunology. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Immunology is the official Journal of the International Union of Immunological Societies (IUIS). Encompassing the entire field of Immunology, this journal welcomes papers that investigate basic mechanisms of immune system development and function, with a particular emphasis given to the description of the clinical and immunological phenotype of human immune disorders, and on the definition of their molecular basis.