February 23, 2007

Study adds clues to autism’s gene links

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James Sutcliffe, Ph.D.

Study adds clues to autism’s gene links

Jonathan Haines, Ph.D.

Jonathan Haines, Ph.D.

A team of Vanderbilt Center for Human Genetics Research investigators and colleagues from around the world released findings this week from the largest study to date seeking to identify genes that might increase the risk of autism.

Their findings, which identify two new genetic links that may predispose people to the brain disorder, appeared in the Feb. 18 online edition of Nature Genetics.

Vanderbilt CHGR investigators James Sutcliffe, Ph.D., and Jonathan Haines, Ph.D., teamed with more than 120 scientists from more than 50 institutions representing 19 countries to form the Autism Genome Project (AGP).

“We recognized that the greatest hope for overcoming the complexity of finding these genes was to pool our resources and family DNA samples,” Sutcliffe said.

Autism is a severe developmental disorder that affects approximately one in 150 children, and its cause is largely genetic in origin. Experts believe that many genes may combine together to cause susceptibility to this condition.

The consortium used state-of-the-art “gene chip” technology to look for genetic commonality in autistic individuals culled from almost 1,200 families.

DNA was scanned for copy number variations (CNV), or sub-microscopic DNA insertions and deletions that scientists believe might be involved with this and other common diseases.

“We now suspect that CNV is another genetic factor contributing to development of autism,” Sutcliffe said.

The combination of approaches implicates a previously unidentified region of chromosome 11, and neurexin 1, a member of a family of genes believed to be important in neuronal contact and communication, among other regions and genes in the genome.

The neurexin finding highlights a special group of neurons — called glutamate neurons — and the genes affecting their development and function, which suggests they play a critical role in autism spectrum disorders.

"This is an important step toward understanding how genetics is involved in autism," said Haines, director of the CHGR.

"Now we have our best clues yet as to which genes might be involved. The next step will be to study these genes in detail to determine which ones really influence autism."

Autism Speaks, a non-profit organization dedicated to increasing awareness of autism, and the National Institutes of Health (NIH), funded phase I of the project.

Encouraged by the findings from the initial phase of the AGP, the consortium launched its $14.5 million second phase on Sunday.

In this phase researchers will apply the 'gene-chip' technologies to scan the genome for association with new genetic markers, as well as sub-microscopic CNVs along chromosomes in autism.

These findings will guide high-throughput DNA sequencing experiments designed to pinpoint underlying changes in DNA sequences in autism susceptibility genes. The unprecedented statistical power generated by the AGP will ultimately allow researchers to confirm the role of these genes in autism spectrum disorders.

“We now have important clues to the location of autism susceptibility genes,” Sutcliffe said. “We now believe that a significant portion of autism cases may be caused by small losses or gains of DNA in the genome. For the first time we know that CNVs may be responsible for 10 percent or more of autism cases.”

“The identification of susceptibility genes is the first crucial step in understanding what causes this condition,” said Haines, who, along with Sutcliffe, are also Vanderbilt Kennedy Center investigators.

“As we identify genetic susceptibility factors in autism, we will open up new opportunities to develop and apply better interventions, understand the underlying biology, and consider future prospects for treatment.”

Phase II is being supported by a coalition of public and private groups, including Autism Speaks, the British Medical Research Council (MRC), the Health Research Board of Ireland (HRB), Genome Canada, Canadian Institutes for Health Research (CIHR), and the Hilibrand Foundation.