Navigation Links
Three gene networks discovered in autism, may present treatment targets

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 Children's 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 CHOP's 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.

Hakonarson's 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.

The three gene families found in the current study have notable functional 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 brainprocesses highly relevant to ASDs.

The functional activities identified in the current study are consistent with a recent multicenter study in which Hakonarson participated, published May 1 in the American Journal of Human Genetics. That study, led by scientists from Paris and Toronto, and using Autism Genome Project data, found 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 in these networks have been implicated in other developmental disorders besides autism.

"Even though our own study was large, it captures only about 20 percent of genes causing ASDs," said 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."


Contact: John Ascenzi
Children's Hospital of Philadelphia

Related biology news :

1. Aware Provides Biometrics Software and Services for Three Large-Scale Border Management Systems
2. Thirty teams compete to interpret three families genomes
3. Three new arthropod species have been found in the Maestrazgo Caves in Teruel
4. Research and Markets Announces the Release of Multi-Factor Authentication Market - by Model/Type [Two, Three, Four & Five-Factor], Application & Geography - Forecasts (2012 - 2017)
5. Evolution Marketing Research Grows its Practice with Addition of Three Key Industry Professionals
6. DFG to fund three new research units
7. Largest lake in Britain and Ireland has lost three-quarters of winter water birds
8. Three native aromatics indicated for use in Mediterranean extensive green roofs
9. Three UTSA College of Sciences faculty honored at AAAS Annual Meeting
10. Three new species of yellow-shouldered bats discovered in museum collections
11. Unraveling biological networks
Post Your Comments:
(Date:11/17/2015)... 17, 2015 Pressure BioSciences, Inc. (OTCQB: PBIO) ... and sale of broadly enabling, pressure cycling technology ("PCT")-based ... today announced it has received gross proceeds of $745,000 ... Placement (the "Offering"), increasing the total amount raised to ... additional closings are expected in the near future. ...
(Date:11/12/2015)... Nov. 12, 2015  A golden retriever that stayed ... dystrophy (DMD) has provided a new lead for treating ... the Broad Institute of MIT and Harvard and the ... . Cell, pinpoints a protective ... the disease,s effects. The Boston Children,s lab of ...
(Date:11/12/2015)... LONDON , Nov. 11, 2015   ... and reliable analytical tools has been paving the ... and qualitative determination of discrete analytes in clinical, ... sensors are being predominantly used in medical applications, ... and environmental sectors due to continuous emphasis on ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... - iCo Therapeutics ("iCo" or "the Company") (TSX-V: ICO) ... quarter ended September 30, 2015. Amounts, unless specified ... under International Financial Reporting Standards ("IFRS"). ... Andrew Rae , President & CEO of iCo ... value enriching for this clinical program, but also ...
(Date:11/24/2015)... 24, 2015  Clintrax Global, Inc., a worldwide provider of clinical ... today announced that the company has set a new quarterly earnings ... on quarter growth posted for Q3 of 2014 to Q3 of ... Mexico , with the establishment of an ... --> United Kingdom and Mexico ...
(Date:11/24/2015)... 24, 2015 SHPG ) announced today that ... Piper Jaffray 27 th Annual Healthcare Conference in ... at 8:30 a.m. EST (1:30 p.m. GMT). --> SHPG ... will participate in the Piper Jaffray 27 th Annual Healthcare ... Tuesday, December 1, 2015, at 8:30 a.m. EST (1:30 p.m. GMT). ...
(Date:11/24/2015)... 24, 2015  Twist Bioscience, a company focused ... Ph.D., Twist Bioscience chief executive officer, will present ... December 1, 2015 at 3:10 p.m. Eastern Time at The ... --> --> ... Bioscience is on Twitter. Sign up to follow ...
Breaking Biology Technology: