Autism Gene Networks Could Offer Treatment Targets

After analyzing the DNA from thousands of patients, investigators from Children’s Hospital have uncovered several gene networks that may play 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.

Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics, and his team also found that one of the autism-related gene pathways also affects some patients with attention deficit hyperactivity disorder (ADHD) and schizophrenia, which raises the possibility that a class of drugs may treat particular subsets of all three neurological disorders.

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. Dr. Hakonarson and his team note that recent investigations suggest that up to 400 distinct ASDs exist.

The investigators conducted a genome-wide association study that drew data from CHOP’s genome center as well as from the Autism Genome Project and the AGRE Consortium, both part of the organization Autism Speaks. The study compared more than 6,700 patients with ASDs to over 12,500 control subjects and represents 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 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 glutamate receptor metabotropic (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.

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.

Dr. Hakonarson’s team and other investigators previously reported that 10 percent or more of ADHD patients have CNVs in genes along the GRM pathway, while other teams have implicated GRM gene defects in schizophrenia.

“Even though our own study was large, it captures only about 20 percent of genes causing ASDs,” said Dr. Hakonarson, who added that still larger studies are needed to further unravel the genetic landscape of autism. “However, strong animal data support an important role for the glutamate receptor pathway in socially impaired behaviors modeling ASDs. 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.”

Based on the results of the study, Dr. 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.

The study appeared in the journal Nature Communications.