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Gene Variants Hold New Clues to Autism

Researchers Identify Gene Mutations That May Raise Risk of Autism Spectrum Disorders

By Kathleen Doheny
WebMD Health News

Reviewed By Louise Chang, MD

April 28, 2009 -- Rare genetic mutations are known to increase the risk of autism and autism spectrum disorders (ASD). Now, researchers have identified new and common gene mutations -- also called gene variants -- that also boost the risk of the developmental disorders that affect an estimated one in 150 U.S. children.

"What we mean by common is that the risk variant is present in about 65% of children diagnosed with autism spectrum disorder," says Hakon Hakonarson, MD, PhD, director of genomics research at The Children's Hospital of Philadelphia and the lead author of two of three studies on the topic published online today.

Based on the new research, which included mostly children with an autism diagnosis -- rather than one of the less severe disorders on the autism spectrum -- the newly identified gene variants for autism could account for about 15% of autism diagnoses, Hakonarson estimates. Having the variant does not automatically mean a person will develop autism, he says, as other genetic and environmental factors are thought to come into play; even so, the 15% estimate is substantial, he says.

Just as importantly, the newly identified gene variants found to boost autism risk are involved in facilitating communication between brain cells -- making more credible the suggestions from other autism experts that autism or ASDs are due to abnormal connections between brain cells early in development, Hakonarson says.

Hakonarson's study, a cooperative effort among numerous institutions and co-authored by respected autism researchers nationwide, is published online today in the journal Nature, along with two other studies uncovering more clues to autism -- one also published in Nature and the other in Annals of Human Genetics.

Gene Variant Study

For the first of two studies, Hakonarson and his colleagues conducted a genome-wide association study on 780 families, including 3,101 participants with affected children, and then a second group of 1,204 people with autism or ASD and 6,491 in a comparison group. A genome-wide study involves the scanning of markers across the complete set of the DNA (or genomes) obtained from many people to find genetic variations associated with specific diseases.

"When we looked to see if any particular regions of the genome looked different, only one region came up," Hakonarson tells WebMD. It was in the region of chromosome 5 involving the genes that facilitate cell-to-cell communication -- CDH9 and CDH10. These genes carry codes to produce crucial neuronal cell-adhesion molecules, Hakonarson says. "They sit on the surface of nerve cells and facilitate and create cell-to-cell communication."

No other common gene variants have been identified and replicated in independent studies with the same scientific rigidity, Hakonarson says.

With the new discovery, the hope is to identify children having these variants at birth or even in utero so intervention can begin early, Hakonarson says. Eventually, he says, the goal would be to create specific treatments to correct the gene variant.

DNA Duplications and Autism Risks

In the second study, Hakonarson and colleagues used the same genome-wide association approach to find genes that were either duplicated or deleted in those with autism or ASD. For this study, the researchers looked at 2,195 children with ASD and 2,519 children without ASD.

They found some previously reported genes, but also some new ones.

And the newly discovered gene variants tended to affect genes involved in cell adhesion, linking the findings to those in the first study.

Search for Genetic Variants

In another study, published online in the Annals of Human Genetics, Margaret Pericak-Vance, PhD, director of the Miami Institute for Human Genomics at the University of Miami Miller School of Medicine, searched for small genetic variants associated with ASD also using a genome-wide association approach.

She used a data set of 438 families with autistic children and then validated the findings with another data set of 487 families with autistic children.

"We found basically the same thing as the Nature paper,'' she says. In addition to multiple and rare gene variants, she concludes that part of "complex genetic architecture of autism involves common variation."

She calls the new research "the most significant finding to date, the most universal finding to date, that clearly shows common gene variants can play a role in giving someone a risk for autism."

Gene Variants and Autism: Interpretations

The new research still doesn't give autism researchers the whole picture, says Daniel Geschwind, MD, PhD, one of the principal investigators on the Nature research and director of the Center for Autism Research and Treatment, University of California Los Angeles.

But, he tells WebMD, "Over the last five years, there has been remarkable progress in autism genetics." That's primarily due to the relatively new technique of genome-wide association studies, he says.

"We know that rare genetic variation probably contributes more [to autism risk] than we thought it did," Geschwind says. "This study, looking at common variation, is more evidence that common variation is also involved."

Other research, including his own, has found that other common genetic variations also raises autism risk. "Each common variation is likely to be contributing a small amount," he says.

The new research, Geschwind says, is just the beginning. Information about involvement of specific genes will lead researchers to find the mechanism of the disease. "And the mechanism will lead us to treatment and maybe prevention."

Genetic Risks for Autism: Second Opinion

Together, the three studies provide very useful information, says Thomas Insel, MD, director of the National Institutes of Health's National Institute of Mental Health, who was not a co-author on any of the studies. The National Institutes of Health was one of numerous funding sources for the research.

The study findings don't immediately point to a specific cause or treatments, he says. "If you think about autism as a jigsaw puzzle with 500 pieces, each of these findings is an 'edge' piece." But many edge pieces are needed to make progress, he says.

"It would be a mistake for people to read this and think this is only about genetics," Insel says. "Almost everybody agrees that autism is a collection of different disorders. Some of them may be heavily genetic. But I think most experts would say the bulk of autism is the result of both genetic and environmental effects that are interacting in some way that we have yet to fully describe."

"This begins to fill out the genetic part of the equation."

SOURCES: Hakon Hakonarson, MD, PhD, director, Center for Applied Genomics, The Children's Hospital of Philadelphia; associate professor of pediatrics, University of Pennsylvania School of Medicine. Wang, K. Nature, online, Apr. 28, 2009. Glessner, J. Nature, online, Apr. 28. 2009. Daniel Geschwind, MD, PhD, professor of neurology, psychiatry and human genetics and director, Center for Autism Research and Treatment, University of California Los Angeles David Geffen School of Medicine. Thomas Insel, MD, director, National Institute of Mental Health, National Institutes of Health, Bethesda, Md. Margaret Pericak-Vance, PhD, director, Miami Institute for Human Genomics, University of Miami Miller School of Medicine. Ma, D. Annals of Human Genetics, online Apr. 28, 2009.

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