Systematic Analysis of Protein-Protein and Gene-Environment Interactions to Decipher the Cognitive Mechanisms of Autism Spectrum Disorder.

Autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder resulting from both genetic and environmental risk factors, is manifested by deficits in cognitive function. Elucidating the cognitive disorder-relevant biological mechanisms may open up promising therapeutic approaches. In this work, we mined ASD cognitive phenotype proteins to construct and analyze protein-protein and gene-environment interaction networks. Incorporating the protein-protein interaction (PPI), human cognition proteins, and connections of autism-cognition proteins enabled us to generate an autism-cognition network (ACN). With the topological analysis of ACN, important proteins, highly clustered modules, and 3-node motifs were identified. Moreover, the impact of environmental exposures in cognitive impairment was investigated through chemicals that target the cognition-related proteins. Functional enrichment analysis of the ACN-associated modules and chemical targets revealed biological processes involved in the cognitive deficits of ASD. Among the 17 identified hub-bottlenecks in the ACN, PSD-95 was recognized as an important protein through analyzing the module and motif interactions. PSD-95 and its interacting partners constructed a cognitive-specific module. This hub-bottleneck interacted with the 89 cognition-related 3-node motifs. The identification of gene-environment interactions indicated that most of the cognitive-related proteins interact with bisphenol A (BPA) and valproic acid (VPA). Moreover, we detected significant expression changes of 56 cognitive-specific genes using four ASD microarray datasets in the GEO database, including GSE28521, GSE26415, GSE18123 and GSE29691. Our outcomes suggest future endeavors for dissecting the PSD-95 function in ASD and evaluating the various environmental conditions to discover possible mechanisms of the different levels of cognitive impairment.