UW News

April 30, 2009

Autism genes discovered; help shape connections among brain cells

A national research team including six present and former UW researchers has connected more of the intricate pieces of the autism puzzle, with two studies that identify genes with important contributions to the disorder.

One study pinpoints a gene region that may account for as many as 15 percent of autism cases, while the second study identifies missing or duplicated stretches of DNA along two crucial gene pathways. Significantly, both studies detected genes implicated in the development of brain circuitry in early childhood.

“Because other autism researchers have made intriguing suggestions that autism arises from abnormal connections among brain cells during early development, it is very compelling to find evidence that mutations in genes involved in brain interconnections increase a child’s risk of autism,” said study leader Dr. Hakon Hakonarson, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. The main collaborator on the study is Gerard Schellenberg of the University of Pennsylvania School of Medicine. Schellenberg formerly was a research professor of medicine at the UW and a principal investigator at the UW Autism Center.

Researchers from more than a dozen institutions participated in both studies, which appear in the April 28 advance online edition of the journal Nature.

Autism is the best known of the autism spectrum disorders (ASDs), a group of childhood neurodevelopmental disorders that cause impairments in verbal communication, social interaction and behavior. Currently estimated to affect as many as one in 150 U.S. children, ASDs are known to be strongly influenced by genetics. Previous studies have implicated several chromosome regions harboring rare variants in raising the risk of ASDs, but until now, research has not been consistent in identifying and replicating common genetic variants.

One of the studies is the first to identify common genetic variants associated with autism. By using highly automated genotyping tools that scan the entire genome of thousands of individuals, the researchers found that children with ASDs were more likely than healthy controls to have gene variants on a particular region of chromosome 5. That region is located between two genes, cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry codes to produce neuronal cell-adhesion molecules.

Neuronal cell-adhesion molecules are important because they affect how nerve cells communicate with each other, thought to be an underlying problem in ASDs.

“These molecules are expressed on the cell surfaces of neurons, and they are involved with shaping both the physical structure of the developing brain and the functional connections among different brain regions,” Hakonarson said. “Although a particular gene variant may contribute a small risk for an ASD in a particular individual, we estimate that the variants we discovered may contribute to as many as 15 percent of ASD cases.”

The researchers first performed genome-wide association studies on DNA from more than 3,100 subjects from 780 families of children affected with ASDs, then performed further studies in a cohort of 1,200 affected subjects and 6,500 unaffected controls. They then replicated their results in two additional independent cohorts. In total, they analyzed DNA from 12,834 people.

The second Nature study, also using genomewide association tools, identified copy number variations — deletions or duplications of DNA — that increase a child’s risk of having an autism disorder. Interestingly, these variants were enriched in genes that belong to two biological pathways, one including the same neuronal cell-adhesion molecule gene family that harbored the common variant reported in the first study. The other gene cluster impacted by copy number variations belongs to the ubiquitin degradation pathway. Ubiquitins are a class of enzymes that eliminate connections among nerve cells, and are involved with processing and degrading neuronal cell-adhesion molecules.

“The copy number variations we discovered are active on two gene networks that play critical roles in the development of neuronal connectivity within the central nervous system,” said Hakonarson. “Finding genes that are biologically relevant to these neuronal systems increases our understanding of how autism originates.”

The gene discoveries, he added, converge with evidence from functional magnetic resonance imaging that children with ASDs may have reduced connectivity among neural cells, and with anatomy studies that have found abnormal development of the brain’s frontal lobes in patients with autism.

“Many of the genes we identified concentrate their effects in brain regions that develop abnormally in autistic children,” said Hakonarson. “Our current findings, when coupled with anatomical and imaging studies, may suggest that ASDs are a problem of neuronal disconnection.”

“Someday this type of work will allow us to make early identification of children at risk for autism and provide better treatment outcomes,” said Annette Estes, associate director of the UW’s Autism Center. “To parents this means once the genetic picture is more complete, they will have more certainty about their child’s risk profile, particularly if they already have one child with autism.”

In addition to Estes and Schellenberg, other researchers from the UW who contributed to the studies are Raphael Bernier, Jeffrey Munson and Olena Korvatska and Geraldine Dawson. Dawson, the founding director of the UW’s Autism Center and emeritus professor of psychology, is now the chief science officer of Autism Speaks.

The Children’s Hospital of Philadelphia, the National Institutes of Health and Autism Speaks contributed funding for the study.