In a study published Jan. 23 in Cell, researchers led by Joseph Buxbaum, director of the Seaver Autism Center for Research and Treatment at Mount Sinai, took advantage of better genetic sequencing technologies and one of the largest databases of DNA samples from people with autism to identify 102 genes associated with autism, including 30 that had never before been connected with the condition. The study also distinguished the genes more closely associated with autism from those that might also contribute to other neurodevelopmental disorders including intellectual and motor disabilities.
“This is one of the most important, comprehensive studies on the genetics of autism to date,” says Dr. Geraldine Dawson, director of the Center for Autism and Brain Development at Duke University, who was not involved in the study. “The findings start to put into place a lot of pieces of the autism puzzle.”
The team analyzed more than 35,000 samples, including nearly 12,000 from people with autism that were collected by the Autism Sequencing Consortium, an international consortium of scientists co-founded by Buxbaum that has shared samples and data since 2010. By comparing genetic sequences from people with autism to their siblings, and to people not affected by the condition, the researchers were able to isolate both inherited gene mutations, as well as spontaneous, or de novo, genetic alterations that can arise during development after egg and sperm are fertilized, that could contribute to the condition.
One group of mutations, which stop the gene from making whatever protein or other compound it is supposed to, are the easiest to find, says Buxbaum, because their effect tends to be more obvious.
He and his team went beyond these low-hanging genetic targets and also generated statistical models that could find mutations that don’t shut down a gene’s function completely, but change it slightly. These mutations appear at slightly higher frequencies in the autism samples compared to controls, meaning they could have smaller, but still significant contributions to the autism. Knowing that, says Buxbaum, “now gives us insight into the molecular mechanisms of these genes,” which can, in turn, lead to new ways to treat and mitigate some of the more severe symptoms of autism.
The large number of samples in the study also allowed the researchers to isolate genes that are more intimately associated with autism alone from those that correspond to other conditions, like intellectual disability, language and motor delays that often occur with autism. “From a neurobiological perspective, it’s important to understand whether genes are involved in general cognition or social cognition, as is the case with autism,” Buxbaum says. “Now we have a handful of genes that we can say are really, really autism genes, and much less likely to be intellectual disability genes. That’s a profound neurobiological advance that could be a useful tool for future studies.”
Dawson agrees that the insight into how these altered genes might affect brain function is potentially useful for future autism research. The 102 genes identified seem to be involved broadly in controlling when and how actively genes are expressed, as well as how neurons in the brain communicate with each other. That’s in line with current theories about what contributes to autism; researchers believe an imbalance between brain chemicals that activate and inhibit neuronal signaling can lead to some of the symptoms of the condition.
Ultimately, the added genetic knowledge may lead to new treatments for more severe symptoms of autism. But given the range of genetic factors involved, these strategies may be more personalized than uniform. Dean Hartley, senior director of genomic discovery and translational science for the advocacy organization Autism Speaks, notes that just as there is a range of symptoms for autism, there should be a range of options for considering whether, and how, they should be addressed. “Autism is a spectrum,” he says. “There are a lot of different pathways, and multiple genes and multiple causes of autism. One person may need to be treated differently than another. And by identifying these different genes, we are getting closer to more personalized health care for individuals.
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