A large new analysis of DNA from thousands of patients has uncovered several underlying gene networks with potentially important roles in autism. These networks may offer attractive targets for developing new autism drugs or repurposing existing drugs that act on components of the networks.
Furthermore, one of the autism-related gene pathways also affects some patients with attention-deficit hyperactivity disorder (ADHD) and schizophreniaraising the possibility that a class of drugs may treat particular subsets of all three neurological disorders.
Neurodevelopmental disorders are extremely heterogeneous, both clinically and genetically, said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Childrens Hospital of Philadelphia (CHOP). 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.
The study by Hakonarson and colleagues, appearing online today in Nature Communications, draws on gene data from CHOPs genome center as well as from the Autism Genome Project and the AGRE Consortium, both part of the organization Autism Speaks.
Autism spectrum disorders (ASDs), of which autism is the best known, are a large group of heritable childhood neuropsychiatric conditions characterized by impaired social interaction and communication, as well as by restricted behaviors. The authors note that recent investigations suggest that up to 400 distinct ASDs exist.
The current research is a genome-wide association study comparing more than 6,700 patients with ASDs to over 12,500 control subjects. It was one of the largest-ever studies of copy number variations (CNVs) in autism. CNVs are deletions or duplications of DNA sequences, as distinct from single-base changes in DNA.
The study team focused on CNVs within defective gene family interaction networks (GFINs)groups of disrupted genes acting on biological pathways. In patients with autism, the team found three GFINs in which gene variants perturb how genes interact with proteins. Of special interest to the study group was the metabotropic glutamate receptor (mGluR) signaling pathway, defined by the GRM family of genes that affects the neurotransmitter glutamate, a major chemical messenger in the brain regulating functions such as memory, learning, cognition, attention and behavior.
Hakonarsons team and other investigators previously reported that 10 percent or more of ADHD patients have CNVs in genes along the glutamate receptor metabotropic (GRM) pathway, while other teams have implicated GRM gene defects in schizophrenia.
Based on these findings, Hakonarson is planning a clinical trial in selected ADHD patients of a drug that activates the GRM pathway. If drugs affecting this pathway prove successful in this subset of patients with ADHD, we may then test these drugs in autism patients with similar gene variants, he said.
In ASDs and other complex neurodevelopmental disorders, common gene variants often have very small individual effects, while very rare gene variants exert stronger effects. Many of these genes with very rare defects belong to gene families that may offer druggable targets.
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Three gene networks found in autism, may present treatment targets