Researchers at Stanford and the University of California, Los Angeles have tapped into the genetics of nearly 500 families in the United States to bring new genetic clarity to autism, a neuropsychiatric disorder with notoriously murky roots.
The new study, published in Cell, identifies 16 genes that are involved in understanding how the condition comes to be, said Dennis Wall, PhD, associate professor of pediatrics and of biomedical data science, a co-senior author of the study.
"Past studies have shown that there's reason to believe that autism can be inherited, but that pattern of heritability has yet to be fully understood," said Wall. "With our study, we now have the sample size and structure needed to start understanding what genetic variants are actually part of that heritable risk."
The new study brings scientists a step closer to understanding that pattern, and even finding biomarkers, or a panel of biomarkers, that can flag risk for the developmental condition earlier in life.
The mystery surrounding the genetic origins of autism, Wall said, is in part due to a lack of data. To gather some of that data, Wall and collaborators from UCLA recruited families with children who have autism. Over more than three years, they sequenced and analyzed genetic data from the moms, dads and children, both with and without autism.
Gathering samples from parents and siblings is key, Wall said. It allows the researchers to compare DNA from one individual against another and ultimately find the differences that flag the condition.
"A genetic study this extensive is actually quite uncommon, but it's the best way to decipher the heritable roots of the condition," said Wall. "If you don't have the family structure, it's very difficult to make sense of the molecular factors that play into complex neuropsychiatric genetic disorders. This type of family structure analysis is of high value and could -- and should -- be extended beyond autism to disorders such as as schizophrenia, bipolar disorder or major depression."
In total, the scientists' 16 new genes (the details of which are hosted on the open-access website ihart.org) add to an existing body of genetic mutations already associated with an increased risk for autism, bringing the total to 69 genes. All 69 genes contribute in some way to neurological development or behavior.
"The fact that our genetic analyses turned up genetic mutations already thought to contribute to the development of autism is a strong signal that the new genes we've discovered are legitimate, and not an artifact," said Wall.
The mutations harbored in these 69 genes themselves, however, are not the only genetic factors that can amplify the risk for autism. Other mutations, which are not inherited but occur by chance, known as "de novo" mutations, contribute to the risk for developing the condition. Much of how this works remains unknown.
Researchers do know that children born with certain combinations of these 69 mutations are at a higher risk of developing autism if their DNA also harbors certain de novo mutations.
Exactly what combination and which genes put individuals at the highest risk, however, is something that's yet to be determined. But with this study, Wall and his team have been able to narrow down the pool of suspected genetic factors.
To learn more, Wall and colleagues conducted an experiment in zebrafish investigating one stand-out gene. When this gene was disabled, the fish showed signs of social impairment and irregular sleeping behavior, two common symptoms associated with children who have autism.
"Our next studies will build on this work, and our goal is to develop stronger evidence for genes that flag risk for autism, or even better, could be used in a diagnostic nature," said Wall. "That's the ultimate goal -- to come up with robust gene panels that we can use for genetic testing in the future. While we're making good progress, there's still a ways to go to realize that vision."
Photo by Tyler Nix