Researchers have narrowed down the list of genes implicated in autism spectrum disorder, and they appear to point toward a part of the brain that has largely been overlooked.
Most research into the genetic roots of autism, a highly heritable disorder that affects about 1 in 68 children, starts with a kind of inventory of genes. Then, it narrows down this genome-wide survey to prime suspects that appear to be different among those with one or several of the symptoms of autism.
"What's special about autism is that it doesn't seem like it's a one-gene thing," said Stanford University School of Medicine geneticist Michael Snyder, lead investigator of the study published online Tuesday in the journal Molecular Systems Biology.
"Maybe this is a tough way to look at it," Snyder said of the gene-by-gene approach. "Maybe a better way to look at it is to see what the normal biological landscape looks like, and see how people who are mutated for autism map onto that."
What followed was a complex computational task that corralled proteins into scores of modules tightly bound by their inter-related functions. Then Snyder's team overlaid the map of gene variants implicated in autism.
At first glance, proteins encoded by these 383 suspect genes were scattered among many of these functional modules. But a few of the modules "screamed out" with autism connections, both from existing data and a genome screening the researchers conducted, Snyder said.
One module involved molecular activity that goes on all over the brain, particularly involving synapses, the tiny spaces where electrochemical signals cross for one neuron to another. This helps explain why so much autism research points toward problems with synapses.
But there was another module just as rich in autism implications, and this one implicated the corpus callosum. That thick band of fibers connects the brain's two hemispheres, and it's generally smaller among those with autism – a disease marked by many anomalies in connectivity.
The corpus callosum is chock full of a different kind of brain cell, oligodendrocytes, which provide a sheath of insulation around the transmission lines of neurons, known as their axons. That greatly aids the propagation of electrochemical signals along the neuron. Defects in this myelin sheathing have been associated with developmental disorders.
Further experiments with mice and archived human brain tissue showed that the genes of interest affected the way oligodendrocytes matured and were highly activated in the corpus callosum.
Although the study uncovered 28 previously undescribed genetic links to autism, and confirmed other previously reported links, it still offers no "smoking gun." Researchers will need to delve more deeply into each genetic pathway to better define exactly what goes on there – with the hope of learning how to alter that activity in ways that eliminate symptoms of autism.
The existing results, however, already could help the effort to identify those at risk for the disorder, Snyder said.
"If you can see changes in genes that are associated with a high risk for autism you may be able to catch it early," Snyder said. "The earlier you can diagnose people at risk for this, the better you may be for being able to work with such kids."