背景:骨关节炎(OA)是一种常见的退行性关节疾病,会导致老年人的慢性疼痛和残疾。涉及几个风险因素,如衰老,肥胖,遗传易感性,和环境因素。我们进行了全转录组关联研究(TWAS)和化学相关基因集富集分析(CGSEA)来研究易感基因和环境因素。
方法:通过整合膝关节OA(KOA)和髋关节OA(HOA)的汇总水平全基因组关联研究数据,进行TWAS分析以鉴定易感基因来自基因型-组织表达项目(第8版)的预先计算的表达权重。FUSION软件用于单组织和跨组织TWAS,使用总体柯西关联检验进行组合。使用京都基因和基因组百科全书(KEGG)和基因本体论(GO)数据库探索了TWAS基因的生物学功能和途径。和人软骨mRNA表达谱用于验证TWAS基因。通过将TWAS结果与化学相关基因集整合,进行CGSEA分析以扫描OA相关的化学物质。
结果:在KOA和HOA的7和11条染色体中鉴定出44和93个独特的TWAS基因,分别,其中14个和4个在mRNA谱中显示出显著的差异表达,如CRHR1,LTBP1,WWP2,LMX1B,和PTHLH。在KEGG和GO分析中发现了OA相关通路,如TGF-β信号通路,MAPK信号通路,透明质酸代谢过程,和软骨细胞分化。确定了45种与OA相关的化学物质,包括槲皮素,双酚A,和氯化镉.
结论:通过TWAS和CGSEA分析鉴定了几种候选OA相关基因和化学物质,扩大了我们对基因之间关系的理解,化学品,以及它们对OA的影响。
Osteoarthritis (OA) is a common degenerative joint disease and causes chronic pain and disability to the elderly. Several risk factors are involved, such as aging, obesity, genetic susceptibility, and environmental factors. We conducted a transcriptome-wide association
study (
TWAS) and chemical-related gene set enrichment analysis (CGSEA) to investigate the susceptibility genes and environmental factors.
TWAS analysis was conducted to identify the susceptibility genes by integrating the summary-level genome-wide association
study data of knee OA (KOA) and hip OA (HOA) with the precomputed expression weights from the Genotype-Tissue Expression Project (Version 8). The FUSION software was used for both single-tissue and cross-tissue
TWAS, which were combined using an aggregate Cauchy association test. The biological function and pathways of the
TWAS genes were explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases, and the human cartilage mRNA expression profiles were utilized to validate the TWAS genes. CGSEA analysis was performed to scan the OA-associated chemicals by integrating the TWAS results with the chemical-related gene sets.
There were 44 and 93 unique TWAS genes identified in 7 and 11 chromosomes for KOA and HOA, respectively, fourteen and four of which showed significantly differential expression in the mRNA profiles, such as CRHR1, LTBP1, WWP2, LMX1B, and PTHLH. OA-related pathways were found in the KEGG and GO analysis, such as TGF-beta signaling pathway, MAPK signaling pathway, hyaluronan metabolic process, and chondrocyte differentiation. Forty-five OA-associated chemicals were identified, including quercetin, bisphenol A, and cadmium chloride.
Several candidate OA-associated genes and chemicals were identified through TWAS and CGSEA analysis, which expanded our understanding of the relationship between genes, chemicals, and their impact on OA.