Identification of EIF4A1 as a candidate molecular indicator of autism spectrum disorder using integrative...

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with complex genetic and molecular mechanism. Identifying reliable molecular biomarkers remains a critical challenge. In this study, we integrated mRNA expression profiles from five post-mortem brain tissue GEO datasets to identify ASD-associated genes. Following batch effect correction, differentially expressed genes (DEGs) were analysed and Weighted Gene Co-expression Network Analysis (WGCNA) was performed to screen genes correlated with ASD. Then, five machine learning algorithms - Random Forest, LASSO, Boruta, CatBoost, and LightGBM - were applied to screen hub genes. Lastly, alterations of the hub gene(s) were investigated with a maternal immune activation (MIA) rat model using poly I:C by measuring mRNA expression of the hub genes in the rat nucleus accumbens (NAc) and caudate putamen (CPu). A total of 30 DEGs and 54 WGCNA module genes were identified, yielding 29 key candidates by intersecting these two gene sets. EIF4A1 (Eukaryotic Translation Initiation Factor 4A1) was the sole gene consistently ranked among the top five by all five machine learning algorithms. Analysis of the integrated dataset confirmed that EIF4A1 mRNA expression was significantly elevated in ASD subjects. Finally, using the MIA rat model of ASD, we found that EIF4A1 mRNA expression was significantly down-regulated in the NAc and CPu, and this deficit was rescued by treatment with the antipsychotics olanzapine or risperidone. In conclusion, the present study positions EIF4A1 as a promising candidate molecular indicator with potential implications for understanding disease mechanisms and developing targeted interventions of ASD.