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Updated: Dec 11, 2025
A Pathway Association Study Tool for GWAS Analyses of Metabolic Pathway Information
Published on: July 1, 2020
Integrated Bioinformatics Analysis Reveals Potential Pathway Biomarkers and Their Interactions for Clubfoot
Jing Ding1, Zhenpeng Liang1, Weijia Feng1
1Department of Pediatric Orthopaedics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland).
Insights
Congenital talipes equinovarus (clubfoot) pathogenesis remains unclear. Bioinformatics analysis identified apoptosis, cell contraction, and immune responses as key functions, suggesting new etiological mechanisms beyond traditional hypotheses.
Area of Science:
- Genetics and Bioinformatics
- Developmental Biology
- Pediatric Orthopedics
Background:
- Congenital talipes equinovarus (clubfoot) is a common pediatric skeletal anomaly affecting 1 in 1000 newborns.
- The precise etiology and pathogenesis of clubfoot are not fully understood despite extensive research.
Purpose of the Study:
- To investigate the underlying molecular mechanisms and signaling pathways involved in clubfoot development using integrated bioinformatics analyses.
- To identify potential new etiological factors contributing to clubfoot.
Main Methods:
- Utilized bioinformatics tools (Profiler, NetworkAnalyst, WebGestalt) to analyze enriched signaling pathways.
- Integrated data from Gene Ontology (GO), Human Phenotype Ontology (HP), KEGG, Reactome, and WikiPathways databases.
- Examined gene-gene interactions and transcription factor (TF)-miRNA co-regulatory networks.
Main Results:
- Identified apoptosis (programmed cell death), muscle contraction, metabolism, and immune system functions as prominent.
- Top biological processes included embryo/organ morphogenesis, cell/muscle contraction, and apoptosis.
- Discovered complex interactions within genes, pathways, and TF-miRNA networks, with specific transcription factors regulating key genes.
Conclusions:
- Bioinformatics findings support existing hypotheses regarding ECM, fetal movement, genetic, muscle, neurological, skeletal, and vascular abnormalities.
- New potential etiological mechanisms include cellular/immune responses to stimuli, molecular transport, and metabolism in clubfoot development.
Abstract:
BACKGROUND Congenital talipes equinovarus (clubfoot), one of the most regular pediatric congenital skeletal anomalies, seriously affects the normal growth and development of about 1 in 1000 newborns. Although it has been investigated widely, the etiology and pathogenesis of clubfoot are still controversial. MATERIAL AND METHODS g: Profiler, NetworkAnalyst and WebGestalt were used to probe the enriched signaling pathways by using the Gene Ontology (GO), Human Phenotype Ontology (HP), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome (REAC), and WikiPathways (WP) databases. Large numbers of enriched signaling pathways were identified using the integrated bioinformatics enrichment analyses. RESULTS Apoptosis or programmed cell death (PCD), disease, muscle contraction, metabolism, and immune system were the top functions. Embryo or organ morphogenesis and development, cell or muscle contraction, and apoptosis were the top biological processes, and cell/muscle contraction and apoptosis were the top molecular functions using enriched GO terms analysis. There were a large number of complex interactions in the genes, enriched pathways, and transcription factor (TF)-miRNA co-regulatory networks. Transcription factors such as FOXN3, GLI3, HOX, and NCOR2 family regulated the gene expression of APAF1, BCL2, BID, CASP, MTHFR, and TPM family. CONCLUSIONS The results of bioinformatics enrichment analysis not only supported the previously proposed hypotheses, e.g., extracellular matrix (ECM) abnormality, fetal movement reducing, genetic abnormality, muscle abnormality, neurological abnormality, skeletal abnormality and vascular abnormality, but also indicated that cellular or immune responses to external stimulus, molecular transport and metabolism may be new etiological mechanisms in clubfoot.
