Autism results from a diverse mix of common and rare genetic variants, many of which act in pathways that form and maintain connections between neurons. That’s the message from the largest genome-wide association studies of autism to date, published online today in Nature.

One of the two new studies, which screened more than 10,000 people, for the first time identifies a cluster of common variants — defined as mutations that occur in five percent or more of the general population — that are more prevalent in people with autism than in healthy controls.

Other research groups have found common variants that are disproportionately prevalent in people with autism. But because their sample sizes have been too small, none have found associations with genome-wide significance.

“This is the first paper with good statistical evidence that shows that some of these common variants are involved [in autism],” says lead investigator Gerard Schellenberg, professor of pathology and laboratory medicine at the University of Pennsylvania.

Although this is the first confirmation of common variants associated with autism, researchers have for some time been expecting to find them.

“[The work] is an important step because it underscores what many of us believe,” says Mark Daly, associate professor at the Massachusetts General Hospital who was not involved in either study. “All [types of variants] provide us little pieces of the puzzle and little leverage points with which we can learn about the biology of the disease.”

The study found common variants located between two genes on chromosome 5 — cadherin 9 (CDH9) and cadherin 10 (CDH10) — which code for membrane proteins necessary for brain cell communication.

In the second study, a scan of 2,268 of the same participants, the researchers found nine new and four previously identified copy number variations (CNVs) — large deletions or duplications of DNA — associated with autism.

Interestingly, these CNVs are all involved in one of two major biological pathways: one pathway that’s related to CDH9 and CDH10 function, and another — known as the ubiquitin pathway — that degrades proteins at the synapse, the junction between neurons. Both pathways are important for forming healthy neuronal connections, a developmental process that may go awry in people with autism.

“A lot of people think, and I agree, that autism is a developmental problem where the brain’s wiring diagram has been scrambled a bit. These are the kind of proteins that help either get [the wiring] right, when they’re working well, or not get it right, when they’re not working well,” Schellenberg says.

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