Perturbations of PI3K/AKT, RAS/ERK, WNT/B-catenin networks in leukocytes are linked to ASD genetics and fetal origins of autism

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 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/-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. Leukocyte gene expression levels were analysed in autistic and typically developing infants and toddlers Diagnosis key: ASD: autism spectrum disorder TD: typically developing (control) PDDNOS: pervasive developmental disorder not otherwise specified PreemieNoDelay: Preemie No Delay (the individual was a preemie but didn't show any mental delay) LD: language delay AutFeat: Autism features (individual shows some signs of autism, but doesn't meet full criteria) ADOS_CoSo: the score of each individual for ADOS communication and social deficit, a metric used for the diagnosis of individuals with autism. The higher the score, the more severe the case. These data have been included in a SuperSeries with GSE42133 because the data were normalized together and are linked to that data set.