Genetic Risk for Autism Highlighted in New Research

Two new studies highlight the complex genetic roots of autism. The first says inheriting abnormal mutations of two common genes can raise the risk for developing the disease.

Both genes are most active in the brain's frontal lobe region, responsible for complex social behavior and abstract thought, and are normally involved in the proper functioning of healthy brain cell connections.

They also play a key role in the formation of those connections, or synapses, which allow brain cells to communicate and enable learning, cognition, and memory.

The second study found that the risk for autism may rise in rare instances when normal DNA variations disturb genes along a particular neural pathway that is linked to smooth nervous system development and synapse function.

Geraldine Dawson, Ph.D., a co-author of both studies and the chief science officer of Autism Speaks, an international funder and advocate for biomedical autism research, says, "By using state-of-the-art technology and large samples, we discovered new genes that appear to increase susceptibility to autism."

"The main point," she says, "is that these genes appear to act in conjunction with other genes - some of which are identified already, but most of which are not yet identified - to impact on the way synapses, or brain cell connections, are made.

"And the other point is that the genes that were found are associated with a specific pathway in the brain," says Dr. Dawson. "And this is important in that we might eventually be able to begin to develop treatments to target this specific biochemical pathway."

Learning the Basic Biology of Autism

Dr. Dawson worked in collaboration with Dr. Hakon Hakonarson, director of the Center for Applied Genomics at the Children's Hospital of Philadelphia and the study's leader. Other researchers included Gerard D. Schellenberg, Ph.D., at the University of Pennsylvania; and Kai Wong, Ph.D., also at Children's Hospital.

Drs. Hakonarson, Schellenberg, and Wong presented the findings in the medical journal Nature.

"This is the first crack in the facade of this disease," says Dr. Schellenberg. The findings represent "the next step in understanding the fundamental molecular biology of what's happening in autism."

"And this really gets us a major jump, we think, in terms of knowing what targets to look at," he notes, referring to the development of therapies to combat both the risk for and onset of autism.

For the first study, the researchers conducted a genetic analysis of more than 10,000 children, 4,500 of whom had a diagnosis of autism spectrum disorder, a grouping of neural developmental problems involving verbal skills as well as social interaction and behavior.

The effort yielded two autism-associated culprits - variants of the CDH10 and CDH9 genes - which the researchers suggested could underlie the risk for autism in about 15 percent of cases.

For the second study, researchers looked specifically at the genetic "roadmap" of children with autism spectrum disorder and isolated two genes along the so-called "ubiquitin pathway" - the UBE3A and PARK2 genes - that appeared vulnerable to deletion/replication variations.

The variations seemed to undermine the genes' ability to ensure smooth cell communication across brain synapses. That study involved 859 children with an autism spectrum disorder and more than 1,400 children without this disorder.

Genetics May Combine with Environmental

Collectively, these findings emphasize the complexity of the genetic underpinnings of autism, the researchers say. And they stressed that having these genetic predispositions does not necessarily mean a higher risk for the disorder in the absence of other critical factors.

"We think that, in most cases, autism is caused by a combination of several genes, and they may interact with environmental factors that we have not yet identified," Dr. Dawson says.

"So you could think about it as you would the risk for a heart attack," she says. "If you have high cholesterol alone and you go to your doctor, he may not be too worried. But if you have several risk factors - high cholesterol plus high blood pressure - the risk for getting the disease is much higher."

"So these are one of a set of genes associated with autism risk," explains Dr. Dawson. "And if you inherit the whole set, you would have a higher risk for developing the disease. But you can have these particular genes and not have a higher risk for autism."

Despite that, the findings still hold much to be excited about.

"Even though there appear to be many different genes involved in autism, what is very interesting is that the genes we're finding are clustering around the same brain function - namely, the connections between brain cells," Dr. Dawson says.

"This is important because, when we learn new things or form memories or learn new skills, we do this by creating new connections between cells," says Dr. Dawson. "So if there is a problem doing this, then this will affect our ability to engage in complex behaviors and learn new skills. And this could explain why people with autism have cognitive delay and have such difficulty learning new things.

"So we're getting a better picture now of what contributes to autism," she adds.

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