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Complex gene interactions account for autism risk

Using a novel analysis of the interactions among related genes, Duke University Medical Center researchers have uncovered some of the first evidence that complex genetic interactions account for autism risk. The Duke team found that the brain mechanism that normally stops or slows nerve impulses contributes to the disease.

The team's findings implicate the so-called GABA receptor genes, which are genes that code for key components of "off switches" in the brain's neurons. GABA, or gamma aminobutyric acid, is a neurotransmitter ?a chemical that one neuron fires at receptors on another neuron to trigger a response ?in this case an inhibitory response. GABA receptors are protein switches nestled in nerve cell membranes that are triggered by GABA to cause such inhibition.

Importantly, the study found that the GABA brain system most likely exerts its influence via complex gene-gene interactions.

The current findings, and others that might result from the team's new approach, may ultimately point to methods for early diagnosis of autism, and perhaps new autism therapies, according to the researchers.

"Identifying the genes that contribute to cause autism has been challenging," said Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics. "One explanation is that many genes are involved, none of which individually may have a major effect." At least ten genes ?and possibly as many as a 100 ?are hypothesized to be involved in autism, she said.

"In addition, autism may stem not from the effects of single genes, but rather from the interaction of particular genes, or sets of genes, when they come together in certain combinations," Pericak-Vance added. The analytical method applied by the researchers allowed them to rigorously test for the role of such gene combinations in autism for the first time, she said.

The researchers reported their findings in the September issue of The American Journal of Human Geneti cs (available online August 3, 2005). The work was supported by the National Institutes of Health, the National Alliance of Autism Research, and the Hussman Foundation. Resources were also provided by The Autism Genetic Resource Exchange, a program of Cure Autism Now.

In recent years, the number of children diagnosed with autism in the United States has skyrocketed, the researchers noted. One of the most heritable of complex genetic disorders in neuropsychiatry, autism is characterized by impairments in social interaction and communication and restricted and repetitive patterns of interest or behavior.

While many previous studies have identified possible genes with links to autism, there remains no single gene with a consistent connection to the disease, Pericak-Vance said.

Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in patients with autism, have implicated the brain mechanism in the disease. Furthermore, there is evidence that GABA plays a key role in the early development of the brain.

Earlier research by the Duke team and other researchers linked a portion of chromosome 15 to autism risk. That region harbors genes that code for three GABA receptors.

Since one of the primary functions of GABA is to inhibit nerve cells from firing, it plays a key role in telling the body to "slow down.". The GABA system therefore acts as a sort of information filter, preventing the brain from becoming over-stimulated, the researchers explained.

"Impairing the GABA system could overwhelm the brain with sensory information, leading to both the behavior and the pattern of cell damage that emerges in autism," said John Hussman, Ph.D., a study co-author and president of The Hussman Foundation, one of the groups that funded the study.

The researchers examined 14 genes that encode portions of the GABA receptor in 470 Caucasian families. Of those families, 266 included more than one person wi th autism and 204 included one autistic individual. The team tested for associations between particular gene variants and the disease. They also applied sophisticated statistical methods designed to zero in on the effects of particular gene combinations.

The researchers found that one of the GABA receptor genes, GABRA4, is involved in the origin of autism. Moreover, they report, GABRA4 appears to increase autism risk through its interaction with a second GABA gene, GABRB1.

"This is a key finding for our understanding of the complexity of interactions that underlie autism," Pericak-Vance said. "We can now apply the analytical approach to other genes that may play a role in the disease." Such findings may ultimately yield a method to screen for individuals at high risk for the disease, she added.

"The new findings offer important new information for families affected by autism about the complexity of the disease," said clinical psychologist Michael Cuccaro, Ph.D., a study co-author also of the Duke Center for Human Genetics.

Furthermore, he added, existing medications already target the GABA system, including diazepam (ValiumĀ®) and some anti-epileptic drugs. "As we begin to understand the GABA system as it relates to the neurological underpinnings of autism, we may advance toward new therapies."

Collaborators on the study include D.Q. Ma, P.L. Whithead, M.M. Menold, E.R. Martin, A.E. Ashley-Koch, G.R. DeLong and J.R. Gilbert, all of Duke; H. Mei of North Carolina State University; M.D. Ritchie of Vanderbilt University; and H.H. Wright, Ruth Abramson of University of South Carolina.


Source:Duke University Medical Center

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