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Autism Transcriptomic Analysis Uncovers Altered Gene Network

NEW YORK – A key gene network is disrupted in autism spectrum disorder, according to a new transcriptomic analysis. The analysis further indicated the degree of disruption to the network correlated to disease severity.

By comparing the transcriptomes of toddlers with ASD to those from toddlers with typical development, researchers from the University of California, San Diego, zeroed in on a dysregulated gene network among the toddlers with ASD. This network, they reported today in Nature Neuroscience, was associated with high-confidence ASD risk genes. They suggested that the ASD risk genes might regulate the dysregulated gene network through the RAS-ERK, PI3K-AKT, and WNT- β-catenin signaling pathways.

"The genetics of ASD are extremely heterogeneous," co-senior author Nathan Lewis, an associate professor of pediatrics and bioengineering at UCSD, said in a statement. "Hundreds of genes have been implicated, but the underlying mechanisms remain murky."

But their findings, he added, show that ASD-related genes dysregulate a core network involved in early brain development and that this perturbation has later ramifications for ASD symptom severity.

He and his colleagues analyzed the blood leukocyte transcriptomes of 226 male toddlers, 119 of whom had ASD and 107 of whom had typical development. They uncovered 1,236 differentially expressed genes and used this to tease out network-level transcriptional perturbations.

By overlaying this network onto RNA-sequencing data from the BrainSpan Atlas, the researchers found that their network was enriched for genes that are highly expressed in the neocortex during the prenatal and early postnatal periods, which are thought to be key time points in autism development.

However, the researchers found that their network was not enriched for ASD risk genes. Instead, their network was enriched for the regulatory targets of those risk genes, and the researchers noted that the ASD risk genes likely regulate their network.

"Our evidence suggests that abnormal signals from known ASD risk genes may be channeled through this important gene network," first author Vahid Gazestani, a postdoc at UCSD, added in a statement, "and that, in turn, sends signals that alter fetal and postnatal brain formation and wiring patterns."

Key pathways in this network include the RAS-ERK, PI3K-AKT, and WNT-β-catenin signaling pathways. These signaling pathways have known roles in brain development and are involved in processes ranging from neural proliferation and neurogenesis to neural migration and maturation.

The researchers also compared patterns of network dysregulation to symptoms in toddlers with ASD, using the Autism Diagnostic Observation Schedule Social Affect severity score, a standardized measure of disease severity. The more disrupted their network was, the more severe the toddlers' scores, the researchers reported. This suggested to them that perturbations of the same network, though to different extents, could account for some of the variability observed clinically in toddlers with ASD.

These findings, the researchers said, could inform efforts to develop ways to diagnose children with ASD earlier. Currently, ASD diagnoses rely on behavioral traits that emerge as children age and can be variable, making diagnoses difficult.

"There is an urgent need for robust tests that can identify the disorder and its expected severity at very early ages so that treatment can start early, enabling a better outcome for each child," co-senior author Eric Courchesne, a professor of neuroscience and co-director of the UCSD Autism Center of Excellence, said in a statement.