1. A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity
- Author
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Linda Lopez, Eric Courchesne, Tiziano Pramparo, Sarah S. Murray, Benjamin P. Kellman, Nathan E. Lewis, Vahid H. Gazestani, Srinivasa Nalabolu, and Karen Pierce
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Male ,genetic structures ,Autism Spectrum Disorder ,MAP Kinase Signaling System ,Population ,Gene regulatory network ,Biology ,behavioral disciplines and activities ,Article ,Transcriptome ,Fetal Development ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Neural Stem Cells ,mental disorders ,medicine ,Leukocytes ,Humans ,Gene Regulatory Networks ,Induced pluripotent stem cell ,education ,Protein kinase B ,Wnt Signaling Pathway ,PI3K/AKT/mTOR pathway ,beta Catenin ,030304 developmental biology ,Genetics ,0303 health sciences ,education.field_of_study ,General Neuroscience ,Wnt signaling pathway ,Brain ,Infant ,medicine.disease ,Oncogene Protein v-akt ,030104 developmental biology ,Autism spectrum disorder ,Catenin ,Child, Preschool ,Mutation ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
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/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.
- Published
- 2019