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CHOP-led Team Describes Altered Autism Networks

NEW YORK (GenomeWeb News) – A Children's Hospital of Philadelphia-led team has identified autism spectrum disorder-related changes in three interacting gene sets, spelling out details about the biological processes behind the neuropsychiatric conditions.

As they reported in Nature Communications, the researchers used copy number variant information and gene family interaction network analyses to look for ASD-related pathways containing potential treatment targets.

Based on genome-wide copy number variant profiles for 6,742 individuals with ASD and 12,544 unaffected controls, they saw a jump in ASD-related alterations affecting networks previously implicated in cancer, neuronal synapse signaling, and other neurodevelopmental conditions — namely attention deficit hyperactivity disorder and schizophrenia.

"Neurodevelopmental disorders are extremely heterogeneous, both clinically and genetically," senior author Hakon Hakonarson, director of CHOP's Center for Applied Genomics, said in a statement. "However, the common biological patterns we are finding across disease categories strongly imply that focusing on underlying molecular defects may bring us closer to devising therapies."

Hakonarson and his colleagues performed their gene network interaction analysis using array-based CNV patterns gleaned from Illumina HumanHap genotyping on ASD cases and controls.

More than 5,000 of the cases and all 12,544 of the unaffected controls were tested at CHOP, the study's authors noted, while almost 1,700 individuals with ASD were genotyped through the Autism Genome Project. The analysis also included information provided by the Autism Genetic Research Exchange consortium and by published ASD studies.

The data made it possible to look at the nature and numbers of CNVs found in cases compared to controls in individuals with the same ancestry and from multi-ethnic cohorts.

In addition to tracking down specific loci linked to ASD, the team considered the network context of the ASD-related sites, uncovering an over-representation of CNVs in genes from three pathways in the ASD cases. These included a set of cancer-associated genes in the MXD-MYC-MAX network and a network of calmodulin 1-related genes contributing to neuronal synapse function.

The gene network interaction analysis also pointed to a propensity for changes affecting members of the metabotropic glutamate receptor, or GRM, signaling pathway in individuals with ASD. That pathway mediates movement of a neurotransmitter called glutamate, the researchers noted, and past studies suggest that it tends to be upended in individuals with ADHD or schizophrenia.

Hakonarson and his team have their eye on ADHD treatments that target the GRM network. Depending on results from an ADHD trial of such therapies, he said there is a possibility of testing similar drugs for some individuals with ASD.

"Because the GRM pathway seems to be a major driver in three diseases — autism, ADHD and schizophrenia — there is a compelling rationale for investigating treatment strategies focused on this pathway," Hakonarson said in a statement.