JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

Abstract Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by marked genetic heterogeneity. This study aimed to use gene expression datasets to explore candidate hub genes for ASD. Methods: In this study, two independent microarray datasets of the cerebellum of children with ASD were integratively analysed using NetworkAnalyst to screen crucial candidate genes and related signalling pathways. Upregulation of the two hub genes was validated by other datasets and an ASD mouse model. Results: NetworkAnalyst identified two upregulated genes as the most crucial genes in the cerebellum of children with ASD: Jun proto-oncogene (JUN) and platelet-derived growth factor receptor alpha (PDGFRA). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, genes associated with JUN in the cerebellum highlight the pathways of Th17 cell differentiation and Th1 and Th2 cell differentiation. Genes associated with PDGFRA in the cerebellum were enriched in the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and Rap1 signalling pathways. The analysis of all the differentially expressed genes (DEGs) of the two datasets using gene set enrichment analysis (GSEA) demonstrated the involvement of the IL-17 signalling pathway, which is related to the expression of JUN and PDGFRA. ImmuCellAI found that elevated expression of JUN and PDGFRA correlated with the abundance of Th17 and monocytes, suggesting that JUN and PDGFRA could regulate Th17 cell activation and monocyte infiltration. Our ASD mouse model of maternal immune activation demonstrated that JUN and PDGFRA were upregulated in ASD mice. Limitations: The function of JUN and PDGFRA in patients of ASD and different ASD mouse models require explore and validation, and the results should be replicated in more patients with ASD. Conclusions: JUN and PDGFRA are crucial candidate genes and related to the IL-17 signalling pathway in ASD patients.