Integrating transcriptome-wide association study and mRNA expression profile identified candidate genes related to hand osteoarthritis

Xu, Jiawen; Zeng, Yi; Si, Haibo; Liu, Yuan; Li, Mingyang; Zeng, Junfeng; Shen, Bin

doi:10.1186/s13075-021-02458-2

Cited by 15 publications

(10 citation statements)

References 35 publications

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“…On the other hand, the distinguished clinical appearance between male and female patients warrants the mechanistic investigation at the molecule level. In the current study, the global gene expression profiles of knee joint articular cartilage from male and female donors of a well-accepted dataset [33][34][35][36][37][38][39][40][41][42], GSE114007, were comprehensively compared to gain insight into the understanding of the SABV not only in the healthy status, but also in the response of OA stimulation.…”

Section: Discussionmentioning

confidence: 99%

Males and Females Have Distinct Molecular Events in the Articular Cartilage during Knee Osteoarthritis

Zheng

2021

IJMS

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Osteoarthritis (OA) is a major public health challenge that imposes a remarkable burden on the affected individuals and the healthcare system. Based on the clinical observation, males and females have different prevalence rates and severity levels of OA. Thus, sex-based differences may play essential roles in OA’s prognosis and treatment outcomes. To date, the comprehensive understanding of the relationship between sex and OA is still largely lacking. In the current study, we analyzed a published transcriptome dataset of knee articular cartilage (GSE114007) from 18 healthy (five females, 13 males) and 20 OA (11 females, nine males) donors to provide a slight insight into this important but complex issue. First, comparing female healthy cartilage samples with those of males revealed 36 differential expression genes (DEGs), indicating the fundamental sex-related differences at the molecular level. Meanwhile, 923 DEGs were distinguished between OA and healthy female cartilage, which can be enriched to 15 Reactome pathways. On the other hand, when comparing OA and healthy male cartilage, there are only 419 DEGs were identified, and only six pathways were enriched against the Reactome database. The different signaling response to OA in the male and female cartilage was further enforced by recognizing 50 genes with significantly different OA-responsive expression fold changes in males and females. Particularly, 14 Reactome pathways, such as “Extracellular matrix organization”, “Collagen biosynthesis and modifying enzymes”, “Dissolution of fibrin clot”, and “Platelet Aggregation (Plug formation)”, can be noted from these 50 sex-dependent OA-responsive genes. Overall, the current study explores the Sex as a Biological Variable (SABV) at the transcriptomic level in the knee articular cartilage in both healthy status and OA event, which could help predict the differential OA prognosis and treatment outcome of males and female patients.

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Section: Discussionmentioning

confidence: 99%

Males and Females Have Distinct Molecular Events in the Articular Cartilage during Knee Osteoarthritis

Zheng

2021

IJMS

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“…As a powerful genebased method, TWAS has been successfully applied to decipher the genetic architecture of several complex traits. [9][10][11][12] The majority of existing TWAS studies calculated genetic-expression matrix in each tissue separately, which might neglect the sharing local regulation of gene expression across different tissues. 13 Evidence has shown that eQTL with large effects can regulate gene expression across multiple tissues.…”

Section: What This Study Addsmentioning

confidence: 99%

Novel insight into the aetiology of rheumatoid arthritis gained by a cross-tissue transcriptome-wide association study

Wang

Yin

et al. 2022

RMD Open

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BackgroundAlthough genome-wide association studies (GWASs) have identified more than 100 loci associated with rheumatoid arthritis (RA) susceptibility, the causal genes and biological mechanisms remain largely unknown.MethodsA cross-tissue transcriptome-wide association study (TWAS) using the unified test for molecular signaturestool was performed to integrate GWAS summary statistics from 58 284 individuals (14 361 RA cases and 43 923 controls) with gene-expression matrix in the Genotype-Tissue Expression project. Subsequently, a single tissue by using FUSION software was conducted to validate the significant associations. We also compared the TWAS with different gene-based methodologies, including Summary Data Based Mendelian Randomization (SMR) and Multimarker Analysis of Genomic Annotation (MAGMA). Further in silico analyses (conditional and joint analysis, differential expression analysis and gene-set enrichment analysis) were used to deepen our understanding of genetic architecture and comorbidity aetiology of RA.ResultsWe identified a total of 47 significant candidate genes for RA in both cross-tissue and single-tissue test after multiple testing correction, of which 40 TWAS-identified genes were verified by SMR or MAGMA. Among them, 13 genes were situated outside of previously reported significant loci by RA GWAS. Both TWAS-based and MAGMA-based enrichment analyses illustrated the shared genetic determinants among autoimmune thyroid disease, asthma, type I diabetes mellitus and RA.ConclusionOur study unveils 13 new candidate genes whose predicted expression is associated with risk of RA, providing new insights into the underlying genetic architecture of RA.

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“…The effect of genes on immune infiltration was evaluated. The level of immune cell infiltration in each sample was quantified by single sample gene set enrichment analysis (ssGSEA) (24). Spearman correlation analysis was performed on gene expression and immune cell content.…”

Section: Immune Gene Correlation Analysismentioning

confidence: 99%

Weighted gene co-expression network analysis reveals specific modules and hub genes related to immune infiltration of osteoarthritis

Cao¹,

Ding²,

Shang³

et al. 2021

Ann Transl Med

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Background: The incidence of osteoarthritis (OA), a chronic degenerative disease, is increasing every year.There is no effective clinical treatment for OA and the pathological mechanism remains unclear. Early diagnosis is an effective strategy to control the progress of OA. In this study, we aimed to identify potential early diagnostic biomarkers.Methods: We downloaded the gene expression profile dataset, GSE51588 and GSE55235, from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) public database.The differentially expressed genes (DEGs) were screened out using the "limma" R package. Weighted gene co-expression network analysis (WGCNA) was utilized to build the co-expression network between the normal and OA samples. A Venn diagram was constructed to detect the hub genes. Potential molecular mechanisms and signaling pathways were enriched by gene set variation analysis (GSVA). Single sample gene set enrichment analysis (ssGSEA) was used to identify the immune infiltration of OA.Results: We screened out three hub genes based on WGCNA and DEGs in this study. GSVA results showed that nuclear factor interleukin-3 (NFIL3) was related to tumor necrosis factor alpha (TNF-α) signaling via nuclear factor kappa-B (NF-κB), the reactive oxygen species pathway, and myelocytomatosis (MYC) targets v2. Highly-expressed ADM (adrenomedullin) pathways included TNF-α signaling via NF-κB, the reactive oxygen species pathway, and ultraviolet (UV) response up. OGN (osteoglycin)-enriched pathways included epithelial mesenchymal transition, coagulation, and peroxisome.Conclusions: We identified three hub genes (NFIL3, ADM, and OGN) that were correlated to the development and progression of OA, which may provide new biomarkers for early diagnosis.

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Integrating transcriptome-wide association study and mRNA expression profile identified candidate genes related to hand osteoarthritis

Cited by 15 publications

References 35 publications

Males and Females Have Distinct Molecular Events in the Articular Cartilage during Knee Osteoarthritis

Males and Females Have Distinct Molecular Events in the Articular Cartilage during Knee Osteoarthritis

Novel insight into the aetiology of rheumatoid arthritis gained by a cross-tissue transcriptome-wide association study

Weighted gene co-expression network analysis reveals specific modules and hub genes related to immune infiltration of osteoarthritis

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