A perturbed gene network containing PI3K–AKT, RAS–ERK and WNT–β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

On the Nature of Monozygotic Twin Concordance and Discordance for Autistic Trait Severity: A Quantitative Analysis

“…Overall, these findings constitute an identical twin demonstration of a remarkable observation originally reported by Spiker et al (2002) that even in the context of familial recurrence of autism, the specific profile of symptoms among affected individuals do not breed true within families. Very recently, Gazestani et al (2019) observed transcriptomic signatures of leukocytes that differentiated children with autism from typical controls and related to variation in expression of genes implicated in the cause of autism-such epigenetic variation, if replicated, could harbor clues to the mechanisms underlying stochastic and/or non-shared environmental influences on variation-in severity implicated by this study.…”

Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes

“…Genetic theories, such as the oligogenic, polygenic, and omnigenic models, provide invaluable insights into how the genetics of complex diseases could be explained by tissuespecific and broadly-expressed genes. Importantly, these models propose that genetic aberrations for both tissue-specific and broadly-expressed risk genes could converge through gene regulatory networks onto neurodevelopmental processes (Boyle et al, 2017;Califano and Alvarez, 2017;Courchesne et al, 2020;Gazestani et al, 2019). Here we systematically tested this concept for rASD genes.…”

“…Furthermore, the two groups are linked differently to comorbidities associated with ASD. Collectively, we describe here the organization of the genetic architecture of ASD as a hierarchy of broadlyexpressed and brain-specific genes that disrupt successive stages of core neurodevelopmental processes.Recent studies present an alternate model of complex traits where the functional impact of genetic aberrations propagates through gene regulatory networks to converge on downstream core processes related to the trait (Boyle et al, 2017;Califano and Alvarez, 2017;Courchesne et al, 2020;Gazestani et al, 2019;Iakoucheva et al, 2019;Liu et al, 2019). In contrast to the single-group rASD network model, if the polygenic and omnigenic models are relevant to ASD, they would suggest that many risk genes are not necessarily part of underlying neural mechanisms in ASD.…”

“…In contrast to the single-group rASD network model, if the polygenic and omnigenic models are relevant to ASD, they would suggest that many risk genes are not necessarily part of underlying neural mechanisms in ASD. Rather many rASD genes would be broadly-expressed across many tissues, but regulate core neurodevelopmental processes underlying ASD (Boyle et al, 2017;Califano and Alvarez, 2017;Courchesne et al, 2020;Gazestani et al, 2019). Moreover, by emphasizing the gene regulatory networks, these alternative models suggest that, to the extent that the gene regulatory networks are preserved, the dysregulation could also be reflected in non-neuronal cells .…”

Inference and validation of an integrated regulatory network of autism

“…KEGG pathway and GO analysis indicated that mRNAs and miRNAs interacted with the candidate lncRNAs mainly function in synapse organization, synaptic transmission, synapse assembly and regulation of nervous system development. Based on KEGG pathway analysis, several pathways were enriched, including glutamatergic synapse, Wnt signaling pathway, neurotrophin signaling pathway, Hippo signaling pathway and PI3K-Akt signaling pathway which were previously reported as dysregulated in autism (16)(17)(18)(19). This suggests that these candidate lncRNAs might play important and functional roles by interacting with key protein-coding and miRNA genes that in turn may contribute to autism.…”