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| |  Risk of Autism Tied to Genes That Influence Brain Cell Connections BETHESDA, Md -- April 28, 2009 -- In 3 genome-side association studies, including the most comprehensive study of autism genetics to date, investigators have identified common and rare genetic factors that affect the risk of autism spectrum disorders (ASD). The results point to the importance of genes that are involved in forming and maintaining the connections between brain cells. "These findings establish that genetic factors play a strong role in autism spectrum disorder," said Raynard Kington, MD, National Institutes of Health (NIH), Bethesda, Maryland. "Detailed analysis of the genes and how they affect brain development is likely to yield better strategies for diagnosing and treating children with autism." The largest study, reported in the journal Nature, involved more than 10,000 individuals including individuals with ASD, their family members, and other volunteers from across the US. The DNA samples came from a repository called the Autism Genetic Resource Exchange (AGRE), and from subjects recruited at clinics in Pennsylvania, Florida, California, and other sites. Previous studies of twins with ASD, other children with ASD and their relatives provided evidence of a strong genetic contribution. Yet until now, only a few genetic risk factors had been identified, and most of those turned out to be rare, with unclear significance for ASD in the general population. Hakon Hakonarson, MD, University of Pennsylvania School of Medicine, and Center for Applied Genomics at the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, and colleagues found several genetic variants that were commonly associated with ASD, all of them pointing to a spot between 2 genes on chromosome 5, called CDH9 and CDH10. Both genes encode cadherins -- cell surface proteins that enable cells to adhere to each other. The researchers also found that a group of about 30 genes that encode cell adhesion proteins (including cadherins and neurexins) were more strongly associated with ASD than all other genes in their data set. In the developing brain, cell adhesion proteins enable neurons to migrate to the correct places and to connect with other neurons. In a second study, published in the Annals of Human Genetics, Margaret Pericak-Vance, PhD, University of Miami Miller School of Medicine and Miami Institute for Human Genomics, Miami, Florida, and colleagues completed an independent search for small genetic variants associated with ASD. The study provides a striking confirmation that ASD is associated with variation near CDH9 and CDH10. "We are starting to see genetic pathways in ASD that make sense," said Dr. Pericak-Vance. The third study, reported in the journal Nature, Drs. Hakonarson and Gerard D. Schellenberg, PhD, also with the University of Pennsylvania, led a search for genes that were duplicated or deleted in individuals with ASD. In the rare cases where those variations occurred, many tended to affect genes involved in cell adhesion. Others tended to affect genes involved in the ubiquitin-proteasome system, a cellular waste disposal system that probably affects the turnover of adhesion proteins at the cell surface. Previous, smaller genetic studies reported a connection between male-only autism and CNTNAP2, a type of neurexin. Together, the 3 new studies suggest that genetic differences in cell-to-cell adhesion could influence susceptibility to ASD on a large scale. Dr. Hakonarson and his colleagues are planning an even more extensive genome-wide association study to gain a more complete picture of the genes and gene interactions involved in ASD. SOURCE: National Institutes of Health
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