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Gene Alterations May Contribute to Autism Susceptibility

University of Utah psychiatry researchers have collaborated with an international team of scientists to identify novel regions of the human genome that may confer susceptibility to autism and related neurodevelopmental disorders, collectively referred to as autism spectrum disorders (ASDs). These findings represent a breakthrough in autism research, according to two studies published May 28, 2009 in Nature.
The studies, which included 150 Utahns who are part of ongoing ASD research, shed new light on possible biological mechanisms that contribute to the development of autism and may lead to more effective treatments of the disorder.

In the first study, the largest genetic study of autism to date, scientists found a common gene variant that occurs 20 percent more often in autistic children than in typically developing children. This gene variation may disrupt communication between nerve cells and play an important part in 12 percent to 18 percent of autism cases. In the second study, researchers discovered new susceptibility genes not previously linked to ASD.

An estimated one in 150 children in the United States carry a diagnosis of ASD, which comprises a group of childhood disorders characterized by impairments in social and verbal communication skills, repetitive patterns of behavior, and narrow interests. A 2007 study, which also involved University of Utah researchers, found the disorder is more common in Utah, occurring in one in 133 children.
"Autism and other ASDs are a major public health burden," says William McMahon, M.D., professor and chairman of the Department of Psychiatry at the University of Utah School of Medicine and a co-author on both studies. "Previous research has suggested there are strong genetic components that predispose to ASDs, but it has been difficult to identify common genetic risk factors because ASD is so variable and can present in so many different ways."

The common gene variant identified in the first study lies in a region of chromosome 5 near a gene that is highly active during the development of the frontal cortex, the region of the brain necessary for language and judgment. This gene, CHD10, encodes a type of protein, called a neuronal cell-adhesion molecule, which affects how nerve cells communicate with each other.
Previous research has reported autism to be associated with copy-number variation (CNV), a phenomenon in which short segments of DNA are duplicated or deleted in the genomes of autistic children. The second Nature study replicated previously reported CNVs, but also identified new CNVs in genes and genomic regions that are more likely to be disrupted in individuals with autism.
Some of the new CNVs were in genes that code for neuronal cell-adhesion molecules, as found in the first study. Other CNVs were in the ubiquitin family of genes, which code for enzymes that degrade the connections made by neuronal cell-adhesion molecules.  This intriguing link between two gene networks provides additional evidence that autism is caused, at least in part, by abnormal nerve connections in the brain.
"Based on our research, two related gene pathways-neuronal cell-adhesion and ubiquitin-may play significant roles in autism," says Hilary Coon, Ph.D., a co-author on the studies and research professor of psychiatry at the University of Utah. "Next steps will involve determining the relative importance of this genetic variation in individual cases, and how these genes interact with other environmental and genetic factors to cause autism.  We hope that future identification of gene variants associated with ASD will lead to development of genetic tests that could identify children at risk for autism to facilitate critical early intervention."

Judith S.  Miller, Ph.D., associate professor of psychiatry at the University, also was a co-author on the studies, both of which were funded, in part, by the Utah Autism Foundation and Autism Speaks. Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics, Newark, N.J., was the principal investigator on the studies.