Transcriptional organization of autism spectrum disorder and its connection to ASD risk genes and phenotypic variation
Hundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1-4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/{beta}-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.