A perturbed gene network containing PI3K-AKT, RAS-ERK and WNT-β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity.
Vahid H GazestaniTiziano PramparoSrinivasa NalaboluBenjamin P KellmanSarah MurrayLinda LopezKaren PierceEric CourchesneNathan E LewisPublished in: Nature neuroscience (2019)
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- to 4-year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes highly expressed genes during fetal brain development. This network is dysregulated in human induced pluripotent stem cell-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-β-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.
Keyphrases
- autism spectrum disorder
- pi k akt
- signaling pathway
- cell proliferation
- attention deficit hyperactivity disorder
- intellectual disability
- genome wide
- genome wide identification
- epithelial mesenchymal transition
- stem cells
- cell cycle arrest
- endothelial cells
- induced apoptosis
- copy number
- transcription factor
- depressive symptoms
- single cell
- network analysis
- functional connectivity
- drug induced
- stress induced