Autism Spectrum Disorder and Atypical Brain Connectivity: Novel Insights from Brain Connectivity-Associated Genes by Combining Random Forest and Support Vector Machine Algorithm.

It is estimated that approximately one in every 100 children is diagnosed with autism spectrum disorder (ASD) around the globe. Currently, there are no curative pharmacological treatments for ASD. Discoveries on key molecular mechanisms of ASD are essential for precision medicine strategies. Considering that atypical brain connectivity patterns have been observed in individuals with ASD, this study examined the brain connectivity-associated genes and their putatively distinct expression patterns in brain samples from individuals diagnosed with ASD and using an iterative strategy based on random forest and support vector machine algorithms. We discovered a potential gene signature capable of differentiating ASD from control samples with a 92% accuracy. This gene signature comprised 14 brain connectivity-associated genes exhibiting enrichment in synapse-related terms. Of these genes, 11 were previously associated with ASD in varying degrees of evidence. Notably, NFKBIA, WNT10B, and IFT22 genes were identified as ASD-related for the first time in this study. Subsequent clustering analysis revealed the existence of two distinct ASD subtypes based on our gene signature. The expression levels of signature genes have the potential to influence brain connectivity patterns, potentially contributing to the manifestation of ASD. Further studies on the omics of ASD are called for so as to elucidate the molecular basis of ASD and for diagnostic and therapeutic innovations. Finally, we underscore that advances in ASD research can benefit from integrative bioinformatics and data science approaches.