3 Autism Gene Networks Discovered; May Aid In Drug Development
One in every 88 American children suffer from autism and the total number of autistic children in the U.S. is estimated to be 1,000,000, according to CNN. Though genetic factors have been widely blamed, researchers continue to investigate the exact cause of autism spectrum disorders (ASDs). Now, a project, based on large scale DNA analysis, has helped provide more clues. Researchers concluded that several gene networks may be responsible for autism and that targeting these genes may be the key to curing autism disorders.
Furthermore, the study identified a set of genes that are related to autism as well as attention deficit hyperactivity disorder (ADHD) and schizophrenia. This find may be useful in identifying drugs that can be used to target all three types of disorders. The study involved comparing the genetic data of autistic population to a control population. The scientists relied on data collected from the the Children's Hospital of Philadelphia (CHOP) genome center and from the Autism Genome Project and the AGRE Consortium, both part of the organization Autism Speaks. The study is published today in Nature Communications.
According to a press release, study leader Dr. Hakon Hakonarson, director of the Center for Applied Genomics at CHOP said, "Neurodevelopmental disorders are extremely heterogeneous, both clinically and genetically. 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."
ASDs encompass a range of conditions classified as neurodevelopmental disorders and are characterized by significant difficulties in social interaction, communication difficulties, and behavioral challenges. There are up to 400 distinct disorders that come under the ASD category.
The genomic comparisons in this study were made between 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 structural variations in the DNA of a genome or correspond to those regions that have been deleted or duplicated on certain chromosomes. CNVs have been associated with autism so the team focused on CNVs within defective gene family interaction networks (GFINs) — groups of disrupted genes acting on biological pathways.
The team found three GFINs in autistic patients, where variants affected the way these genes interacted with proteins. They focused specifically on 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.
The current research as well as previous researches have shown that more than 10 percent ADHD patients have CNVs in genes along the glutamate receptor metabotropic (GRM) pathway. There is also a link between GRM gene defects and 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.
It has been found that rarer genetic variants cause more pronounced ASDs and other complex neurodevelopmental disorders than more common gene variants. But the silver lining is that these rare genetic variants belong to gene families that can be targeted by drugs.
Each of the three gene families found in the current study have specific roles. The CALM1 network includes the calmodulin family of proteins, which regulate cell signaling and neurotransmitter function. The MXD-MYC-MAX gene network is involved in cancer development and may underlie links reported between autism and specific types of cancer.
Finally, members of the GRM gene family affect nerve transmission, neuron formation, and interconnections in the brain — processes highly relevant to ASDs.
These findings were corroborated by another study conducted by scientists from Paris and Toronto who used the Autism Genome Project data to find hundreds of rare ASD-related gene variants converging on gene networks involved in neuronal signaling, synapse function, and chromatin regulation (a biological process affecting gene expression). Many of the genes identified in this study are known to be associated with other neurological disorders.
According to Hakonarson, more research needs to be conducted to understand the various complex genetic factors involved in autism. "Even though our own study was large, it captures only about 20 percent of genes causing ASDs. 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," she said.
Source: Hakonarson H et al. The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism. Nature Communications. 2014.