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Small Gene Variations Can Increase Risk of Autism

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An increased risk of autism spectrum disorders (ASD) could result from an accumulation of many small, common genetic variations rather than large-effect, rare changes in the genetic code, according to a multicenter team led by researchers at the University of Pittsburgh School of Medicine. Their findings, published today in Molecular Autism, provide new insights into the genetic factors that underlie the neurodevelopmental condition.

Scientists have debated about the genetic contributions that lead to ASD in families where only one individual is affected, called simplex, versus those that have multiple affected family members, called multiplex, said senior author Bernie Devlin, Ph.D., associate professor, Department of Psychiatry, University of Pittsburgh School of Medicine.

"Our team compared simplex, multiplex and unaffected families using sophisticated quantitative genetic techniques," he said. "In families where only one child has an ASD, 40 percent of the risk is inherited while in families with more than one affected child, the risk rises to 60 percent."

For the project, the team examined thousands of DNA samples from families in the Simons Simplex Collection, in which one child but no parent or sibling had an ASD; the Autism Genome Project, in which more than one child had an ASD; and unaffected families enrolled in the HealthABC Program.

In addition to reviewing nearly 1 million gene variations, called single nucleotide polymorphisms (SNPs), to look for inheritance patterns associated with ASD, they also ran computer simulations to plot family trees using 1,000 SNPs that appear to impact the risk of ASD.

"These small gene changes can add up even though individually they do little harm," Dr. Devlin said. "This might explain why parents who do not have autism traits can have children who do."

Other research has shown that autism and related disorders also can arise from spontaneous variations in parental genes prior to conception as well as rare mutations of larger effect that are passed on, he noted. The multiple inheritance patterns could help explain the range of symptoms in the disorder.

The team included researchers from Yale University, the University of Michigan, University of California Los Angeles, Emory University, Harvard University and others. The effort was funded by grants from the Simons Foundation and National Institutes of Health grant MH057881. 

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