PHILADELPHIA—Researchers from more than a dozen institutions, investigating the most comprehensive study of autism genetics to date, have identified missing or duplicated stretches of DNA along two gene pathways and detected genes linked to the development of brain circuitry in children. Funded in part by the National Institute of Health (NIH), the three separate studies have unlocked pieces of the intricate autism puzzle and given an edge to proponents of nature over nurture.
While previous research has suggested autism is a developmental disorder resulting from abnormal connections in the brain, these studies suggest some genetic factors might lead to abnormal connectivity, says Dr. Thomas Insel, director of the NIH National Institute of Mental Health (NIMH).
Investigators in one study discovered a gene region, possibly accounting for as many as 15 percent of autism cases, thus underscoring the critical role gene variants play in forming and maintaining the connections between brain cells.
With autism affecting one in every150 babies born in the United States, three quarters of them boys, researchers have been trying to gain ground on understanding its cause and diagnosing and treating children, earlier. Fifty years ago, the cause of autism was attributed to "refrigerator mothers," a euphemism which explained away genetic factors, and placed the blame on non-nurturing parents.
Autism spectrum disorders (ASD) comprise a group of disorders manifested by social interaction problems, poor verbal communication and repetitive behaviors ranging from severe (autism) to mild (Asperger's syndrome).
This study throws hot water on the "icebox" theory, says Dr. Hakon Hakonarson, a professor at the University of Pennsylvania School of Medicine and director of the Center for Applied Genomics at The Children's Hospital of Philadelphia.
"We now, for the first time, have convincing evidence that there are strong genetic factors, both common and rare, that underlie autism," Hakonarson says. "Many genes are involved in causing autism. In most cases, it's likely that each gene contributes a small amount of risk, and interacts with other genes—and environmental factors—to trigger the onset of disease."
Hakonarson led the first and largest study, involving more than 10,000 subjects, including a control group.
Other principal investigators on the study, reported in Nature April 28, were Dr. Gerard D. Schellenberg, also a professor at the University of Pennsylvania School of Medicine; Dr. Daniel Geschwind, a professor at the University of California-Los Angeles and director of UCLA's Center for Autism Research and Treatment; and Dr. Margaret Pericak-Vance, a professor at the University of Miami Miller School of Medicine and director of the Miami Institute for Human Genomics.
The DNA samples came from a repository called the Autism Genetic Resource Exchange (AGRE), and from subjects recruited at clinics in Philadelphia, Miami, Los Angeles and other sites.
"We used genome-wide association and screened the genome with 550,000 markers to determine if any regions/genes differ between individuals with autism and healthy individuals," Hakonarson says. "We found one common region that is present in 65 percent of autistic children and 13 regions that are rare, only present in a few autism families each."
Hakonarson and his colleagues found several genetic variants commonly associated with ASD, all pointing to a spot between two 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.
"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," Hakonarson says.
The link with cell-adhesion molecules shows that in autism, nerves don't connect normally or break down, he says.
In the second study, Pericak-Vance searched for small genetic variants associated with ASD, in collaboration with Dr. Jonathan Haines, of Vanderbilt University Medical Center in Nashville. Published in the Annals of Human Genetics, the study shows confirmation that ASD is associated with variation near CDH9 and CDH10.
"The study represents a breakthrough as it shows us for the first time that common genetic variants have an effect on the risk of autism," Haines says. "This study presents some of the first clues about the underlying genetic architecture of autism. It is one small piece of the puzzle—but an important one. While the genetic variations that confer risk are indeed passed on from parent to child, each of those risk variations have a very small effect, so some level of risk may be inherited—but not autism itself."
Finally, in the third study, also reported in Nature, Hakonarson and Schellenberg 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.
Together, these three studies suggest that genetic differences in cell-to-cell adhesion could influence susceptibility to ASD on a large scale, and many of the genes identified concentrate in brain regions that develop abnormally in autistic children, says Hakonarson, who plans an even more extensive genome-wide association study for a more complete picture of the genes and gene interactions involved in ASD.
"I'd like to perform a larger study with 10,000 autistic children and 20,000 to 30,000 controls, and find the rest of the genes that underlie autism, and also to translate these novel findings we have now into new therapies," he says.
The findings also bode well for future commercial endeavors such as diagnostic tests and new therapies, Hakonarson says, adding that before long, the medical profession could be able to screen for autism in utero.
"There are companies that are interested already in doing this, but the development will take some time," Hakonarson says. "We don't have all the answers today, but we know of important genes that we can screen for. Most of these are rare variants, and they become more important if they co-exist with the common variants we just found."
