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.

自闭症谱系障碍 (ASD) 是一种由遗传和环境风险因素导致的异质性神经发育障碍，表现为认知功能缺陷。阐明认知障碍相关的生物学机制可能会开辟有希望的治疗方法。在这项工作中，我们挖掘 ASD 认知表型蛋白来构建和分析蛋白质-蛋白质和基因-环境相互作用网络。结合蛋白质-蛋白质相互作用 (PPI)、人类认知蛋白和自闭症认知蛋白的连接使我们能够生成自闭症认知网络 (ACN)。通过对 ACN 的拓扑分析，确定了重要的蛋白质、高度聚集的模块和 3 节点基序。而且，通过针对认知相关蛋白的化学物质研究了环境暴露对认知障碍的影响。ACN 相关模块和化学靶点的功能富集分析揭示了与 ASD 认知缺陷有关的生物过程。在 ACN 中已确定的 17 个中心瓶颈中，通过分析模块和基序的相互作用，PSD-95 被认为是一种重要的蛋白质。PSD-95 及其交互伙伴构建了一个特定于认知的模块。这个中心瓶颈与 89 个认知相关的 3 节点主题相互作用。基因-环境相互作用的鉴定表明，大多数认知相关蛋白与双酚 A (BPA) 和丙戊酸 (VPA) 相互作用。而且，我们使用 GEO 数据库中的四个 ASD 微阵列数据集（包括 GSE28521、GSE26415、GSE18123 和 GSE29691）检测到 56 个认知特异性基因的显着表达变化。我们的研究结果表明未来努力剖析 ASD 中的 PSD-95 功能并评估各种环境条件以发现不同程度认知障碍的可能机制。