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Spring 2014
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Needles in a Haystack
Implicated in rare forms of autism, two genes may play a wider role.
A second-year Alpert medical student is the lead author of a new study that suggests a new genetic pathway to investigate autism. The statistical analysis by Matthew Schwede MD’15; Eric Morrow, MD, PhD, professor of biology and psychiatry and human behavior; and three coauthors found that two genes associated with rare autism-related disorders were jointly linked to more general forms of autism.

Mutations of one gene cause Christianson syndrome, while changes in the other lead to a severe form of autism with epilepsy. In the study, published in Molecular Psychiatry in March, the researchers found a specific pattern of misregulation—increases or decreases in the proteins that the two genes encode—in the brains of children with autism.

“We kind of stumbled on this,” says Schwede, who studied statistics as an undergraduate at Harvard. “At first we were just identifying what was up- and downregulated in autism cerebral cortex in this data set.”

The researchers based their analysis on messenger RNA samples from a bank of brain tissue of children both with and without autism. Messenger RNA indicates how gene expression was regulated in the cerebral cortex.

“In autism I think people get overwhelmed because there are hundreds of different genes,” says Morrow, who studies autism genomics and sees patients with autism at E. P. Bradley Hospital in East Providence. “One of the important things is to find points of convergence where there are events that might be common across different forms”—events such as gene misregulation.

During a summer 2012 research assistantship funded by Alpert Medical School, Schwede, with Morrow’s guidance, pored over the raw data, made available from a University of California, Los Angeles, study. Schwede’s findings caught Morrow’s attention because Morrow has been studying the two genes and the rare conditions they cause. “When we realized that some genes of interest for our lab were altered in the cerebral cortex, we focused the analysis on these genes in particular and how they were related to other processes,” Schwede says.

Schwede also found a significant correlation between the misregulation of the two genes and the downregulation of synapse genes, which is known to occur in autism. His purely statistical analysis does not explain how the misregulation physiologically affects synapse formation or general autism; Morrow plans to research the neural and behavioral effects of the genes’ misregulation in various experimental systems. “That’s a hypothesis that we can take to the mouse,” he says. “When we knock out these genes, how do the synapses change?”

The statistical results show that studying rare forms of autism not only can help patients with those conditions, Morrow says, but also informs research about other forms of autism.

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