Table 1_A splicing-based multitissue association study of joint transcriptomes identified susceptibility genes for osteoarthritis.docx

BackgroundOsteoarthritis (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. MethodsThis 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. ResultsThis 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. ConclusionIntercellular 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.背景 骨关节炎（Osteoarthritis, OA）是全球范围内高发的慢性退行性关节疾病，严重影响患者生活质量并带来沉重的经济负担。尽管全基因组关联研究（Genome-Wide Association Studies, GWAS）已鉴定出多个与OA相关的遗传位点，但这些位点的功能机制仍未明确。整合基因表达与GWAS数据的转录组关联研究（Transcriptome Association Studies, TWAS）为探索OA的遗传基础提供了全新视角。 方法 本研究整合跨组织与单组织TWAS分析，并结合单细胞测序数据，以鉴定并验证与OA相关的关键基因。研究采用UTMOST、FUSION及MAGMA三种方法开展跨组织与单组织分析，同时通过单细胞测序探究潜在转化生长因子β结合蛋白1（latent transforming growth factor beta binding protein 1, LTBP1）在不同细胞亚型中的表达特征、拟时间轨迹及细胞间通讯模式。 结果 本研究筛选出多个与OA相关的候选基因，其中LTBP1在跨组织与单组织分析中均呈现显著关联（错误发现率<0.05，False Discovery Rate, FDR），并被验证为转化生长因子-β（transforming growth factor-beta, TGF-β）信号通路的关键调控因子。单细胞测序结果显示，LTBP1在不同软骨细胞亚型中存在差异表达，且与Notch信号通路的高度富集相关。拟时间分析揭示了LTBP1在软骨细胞分化过程中的动态调控作用。 结论 细胞间通讯分析表明，高表达LTBP1的细胞可激活TGF-β及血管内皮生长因子（vascular endothelial growth factor, VEGF）等多条信号通路，提示其可能通过调控细胞外基质形成与免疫应答参与OA的发病进程。