Integrated analysis of endoplasmic reticulum stress regulators' expression identifies distinct subtypes of autism spectrum disorder

Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in a variety of human diseases. However, their relevance to autism spectrum disorder (ASD) remains largely unknown. Herein, we aimed to investigate the expression patterns and potential roles of the ER stress regulators in ASD. The ASD expression profiles GSE111176 and GSE77103 were compiled from the Gene Expression Omnibus (GEO) database. ER stress score determined by the single sample gene set enrichment analysis (ssGSEA) was significantly higher in ASD patients. Differential analysis revealed that there were 37 ER stress regulators dysregulated in ASD. Based on their expression profile, the random forest and artificial neuron network techniques were applied to build a classifier that can effectively distinguish ASD from control samples among independent datasets. Weighted gene co-expression network analysis (WGCNA) screened out the turquoise module with 774 genes was closely related to the ER stress score. Through the overlapping results of the turquoise module and differential expression ER stress genes, hub regulators were gathered. The TF/miRNA-hub gene interaction networks were created. Furthermore, the consensus clustering algorithm was performed to cluster the ASD patients, and there were two ASD subclusters. Each subcluster has unique expression profiles, biological functions, and immunological characteristics. In ASD subcluster 1, the FAS pathway was more enriched, while subcluster 2 had a higher level of plasma cell infiltration as well as the BCR signaling pathway and interleukin receptor reaction reactivity. Finally, the Connectivity map (CMap) database was used to find prospective compounds that target various ASD subclusters. A total of 136 compounds were significantly enriched. In addition to some specific drugs which can effectively reverse the differential gene expression of each subcluster, we found that the PKC inhibitor BRD-K09991945 that targets Glycogen synthase kinase 3 beta (GSK3B) might have a therapeutic effect on both ASD subtypes that worth of the experimental validation. Our finding proved that ER stress plays a crucial role in the diversity and complexity of ASD, which may inform both mechanistic and therapeutic assessments of the disorder.