In autism, connections are important, new research suggests. Three genetic studies attempting to understand the disorder’s development point to molecules that form and maintain connections between cells.
“Of all the 20,000-plus genes [in the human genome], we’re down to a small family that keeps getting implicated,” says Thomas Insel, director of the National Institute of Mental Health, in Bethesda, Md.
Scientists previously thought it would be easy to identify common genes for common disorders. Given a large enough study size, statistical methods such as genome-wide associations would “pop out genes like olives out of a bottle,” says Steven Moldin, a human geneticist at the University of Southern California in Los Angeles. But until now, scientists have not been able to find a common genetic link among people with autism.
One of the new studies encompasses more than 14,000 people and has uncovered a variant found in about 65 percent of people with autism. More than half of people without autism or related disorders also have the variant, indicating that other genes and environmental factors are necessary to trigger autism. Still, the variant may account for up to 15 percent of autism cases, a team led by researchers at the Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, also in Philadelphia, reports online April 28 in Nature.
This study and an independent study appearing April 28 in the Annals of Human Genetics point to a region on chromosome 5 that is important in autism. The studies identified variants located in a region of the chromosome between two genes encoding cell adhesion molecules called cadherin 9 and cadherin 10.
“This is the first crack in the façade of this disease,” says Gerard Schellenberg of the University of Pennsylvania School of Medicine, a coauthor on the Nature paper.
A group of genes encoding about 30 different cell adhesion proteins, including cadherins and neurexins, showed the statistically strongest association with autism spectrum disorders. The cell adhesion proteins are important for helping neurons migrate to the right place in the brain and form connections with other neurons.
By examining fetal brains, Hakon Hakonarson, Schellenberg and their colleagues found cadherin 10 is made in the frontal cortex, part of the brain thought to be affected by autism. But the team could not detect any changes in the levels of the protein caused by the autism-associated variant. Such changes may be age-dependent and not show up until later in brain development, says Hakonarson, director of the Center for Applied Genomics at the Children’s Hospital of Philadelphia. Signs of autism typically don’t appear until a child is 2 to 4 years old, he says.
Another study, also led by the Philadelphia-based group and appearing online April 28 in Nature, also suggests that rare variations in the number of copies of cell adhesion genes could contribute to autism. This study of rare variants also points to the involvement of genes in a protein-degradation system as being important in autism. That system, known as the ubiquitin-proteasome system, breaks down proteins and may help regulate formation of connections between neurons.
“The findings here are highly consistent with previous theories that autism is caused by defects of connectivity in the brain,” Hakonarson says.
The findings will not have immediate applications for diagnosis or treatment of autism, but may help scientists learn what goes wrong in the brain to cause the disorder, Insel says. “It may be incremental, but it’s real progress.”
