Integrating Network Analysis and Machine Learning Identifies Key Autism Spectrum Disorder Genes Linked to Immune Dysregulation and Therapeutic Targets

Haitang Wang, Xiaofeng Zhu, Hong Zhang, Weiwei Chen

Background: Understanding the genetic mechanisms and identifying potential therapeutic targets are essential for clarifying Autism Spectrum Disorder (ASD) etiology and improving treatments. This study aims to bridge the gap between basic transcriptomic discoveries and clinical applications in ASD research. Methods: Differentially expressed genes (DEGs) of GSE18123 datase were identified. A protein–protein interaction (PPI) network was constructed. Functional enrichment analysis was performed to link genetic loci to relevant biological pathways. Connectivity Map (CMap) analysis was used to predict potential drugs. Furthermore, immune infiltration correlation analysis explored associations between key genes and immune cell subpopulations. Diagnostic performance of top genes was evaluated by receiver operating characteristic (ROC) analysis. Results: The functional enrichment analysis successfully revealed relevant biological processes associated with ASD, while the CMap analysis predicted potential drugs that were consistent with some clinical trial results. Random forest analysis selected ten key feature genes (SHANK3, NLRP3, SERAC1, TUBB2A, MGAT4C, TFAP2A, EVC, GABRE, TRAK1, and GPR161) with the highest importance scores for autism prediction. Immune infiltration analysis showed significant correlations in genes and multiple immune cell types, demonstrating complex pleiotropic associations within the immune microenvironment. ROC curve analysis indicated that most top genes had strong discriminatory power in differentiating ASD from controls, particularly MGAT4C (AUC = 0.730), highlighting its potential as a robust biomarker. Conclusions: This study effectively bridges the basic transcriptomic discoveries and clinical applications in ASD research. The findings contribute to a better understanding of the etiology of ASD and provide potential therapeutic leads. Future research could focus on validating these potential drugs in clinical studies, as well as further exploring the biological functions of the identified genes to develop more targeted and effective treatments for ASD.