Abstract
Autism spectrum disorder (ASD) is a set of complex neurodevelopmental disorders with etiology that remains elusive. Although there is a mounting body of investigation in different brain regions related to ASD, our knowledge about the common and distinct perturb condition between them is at the threshold of accumulation. In this study, based on protein–protein interactions, post-mortem transcriptome analysis was performed with corpus callosum (CC) and prefrontal cortex (PFC) samples from ASD individuals and controls. Co-expression network analysis revealed that a total of seven (four for CC set, three for PFC set) core dysfunctional modules strongly enriched for known ASD-risk genes. Three quarters of them in CC set (M4, M6, M29) significantly enriched for genes annotated by genetically associated variants in our previous whole genome sequencing data. We further determined transcriptional and post-transcriptional regulation subnetwork for each ASD-correlated module, including 47 pivot transcription factors, 130 pivot miRNAs, and 7 pivot lncRNAs. Moreover, there were significantly more interactions between CC-M4, -M6, and PFC-M2, mainly involved in synaptic functions and neuronal development. Our integrated multifactor analysis of ASD brain transcriptome profile illustrated underlying common and distinct molecular mechanisms and the module crosstalk between CC and PFC, helping to shed light on the molecular neuropathological underlying ASD.
Highlights
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by high degree of clinical and genetic heterogeneity
We performed a differential expression (DE) analysis to determine the gene significantly expressed in ASD compared to controls, and a total of 653 and 720 differentially expressed genes (DEGs) were identified for further analysis, in corpus callosum (CC) and prefrontal cortex (PFC) data respectively (|Fold change| > 1.2 and p-value < 0.05, Supplementary Table S1)
Since interacted genes imply co-expression [31], human protein–protein interaction (PPI) subnetwork based on DEGs containing 3,492 interactors for CC set and 3,243 for PFC set were constructed for additional analysis
Summary
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by high degree of clinical and genetic heterogeneity. Consistent with the primary features of ASD, many studies demonstrated the association between brain abnormalities and the disease, yet no clear and common molecular or pathology mechanisms have proved to be Convergent Molecular Pathways in ASD responsible for this disease so far. Animal experiments showed that abnormal brain regions were mainly involved in the temporal lobe, cerebellar cortex, frontal lobe, hypothalamus, and the striatum by 26 different ASD mouse models [3]. Postmortem and structural magnetic resonance imaging studies have highlighted the frontal lobes, amygdala and cerebellum as pathological area in ASD [4]. Several genetic and environmental risk factors have been identified, we do not have a firm understanding of the pathophysiological basis of this complex disease
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