A Novel Directed Acyclic Graph (DAG) Framework for Integrative Causal Analysis for the Pathogenesis of Idiopathic Scoliosis

<i>Background: </i>Idiopathic scoliosis (IS) presented as one of the most common types in adolescent’s and remains a multifactorial disorder with mysterious and poorly understood etiopathogenesis, which posing challenges for early diagnosis and targeted therapy, while directed acyclic graphs (DAGs) offer a transformative method to this disorder. <i>Objectives: </i>This study introduces an innovative DAG based systems biology approach to systematically map causal interactions among genetic, epigenetic, biomechanical, and neuroendocrine factors driving IS progression. <i>Method: </i>By synthesizing evidence from twin studies, epigenomics, mechanobiology, and clinical endocrinology, we construct the first integrated DAG model of IS pathogenesis, validated through a comprehensive review of studies from PubMed, Scopus, Web of Science, and Google Scholar. <i>Results: </i>The analysis identifies three key mechanistic pathways: 1. A genetic-epigenetic cascade involving DNA methylation dysregulation in growth plate chondrocytes, 2. A neuroendocrine-biomechanical feedback loop mediated by leptin hypothalamic pituitary gonadal axis crosstalk, and 3. A Platelet-Derived Growth Factor driven vicious cycle in vertebral microvasculature. <i>Conclusion: </i>The model demonstrates strong predictive power for idiopathic scoliosis. Furthermore, highlight its translational potential through a DAG-guided therapeutic decision and enabling personalized interventions based on the dominant pathogenic pathways. This framework bridges molecular mechanisms with clinical phenotypes and offering a paradigm shift in IS research and patient care.