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Sweeping studies vindicate genetic theory of autism

Simons Foundation

With autism affecting close to one percent of children in the U.S., the urgency to find some sort of explanation for the disorder has never been greater. This week, three studies published in the 9 June issue of Neuron offer a definitive vindication of the theory that spontaneous, or de novo, genetic mutations underlie the development of autism in many families with no history of the disorder.

Two of the new papers, independent microarray studies of unprecedented scale, point to an array of genetic variants that are likely to increase the risk of developing an autism spectrum disorder. Combined, the two studies -- one by a group at Cold Spring Harbor Laboratory in New York led by Michael Wigler, and the other by a consortium of researchers at multiple institutions, headed by Matthew State at Yale University -- paint a portrait of autism as a highly genetically diverse disorder, whose risk of occurrence may by increased by a mutation at any one of several hundred different sites in the human genome.

A gene network analysis in the third paper, by a team headed by Dennis Vitkup of Columbia University, suggests further that despite the genetic diversity of autism, the myriad of genome regions identified by the microarray scans are not all functionally independent, and in many cases appear to perturb a common molecular network. The implicated network is primarily related to synapse development, axon targeting and neuron mobility. "We believe that our functional analysis signifies an important transition between studies of individual rare mutations to analyses of the underlying molecular networks and pathways," Vitkup says. "This analysis," his team writes, "strongly supports the hypothesis that perturbed synaptogenesis is likely to be at the heart of autism."

The Vitkup team's analysis of this network may also contribute to an understanding of why autism spectrum disorders are more than four times as likely to be diagnosed in males as in females. "Our network analysis and the sizes of observed genetic mutations suggest that significantly stronger functional perturbations are required to trigger the autistic phenotype in females compared to males," Vitkup says.

Each of the two microarray teams used a different type of platform to examine the genomes of more than 1,000 'simplex' families: families with just one child with an autism spectrum disorder, as well as unaffected parents and unaffected siblings. The study population was drawn from the Simons Simplex Collection (SSC), a repository of genetic, phenotypic and biological data from simplex families, which was launched by the Simons Foundation several years ago with the express purpose of facilitating the search for rare mutations linked to autism. The SSC now numbers close to 3,000 families, so additional, follow-up studies are expected in the near future.

While most previous genetic studies of families with autism have focused on data from 'multiplex' families, in which more than one family member has an autism spectrum disorder, most cases of autism in fact occur in simplex families. A growing body of evidence suggests that in these families the disorder typically arises from highly deleterious 'de novo' mutations -- mutations that the affected child did not inherit from a parent. Most of these mutations are believed to be extremely rare, appearing in at most one percent of the population on the autism spectrum.

Identifying these mutations in individuals affected by autism may eventually allow researchers to design customized drug therapies that can take on the roles of the damaged genes.

"These studies are the culmination of a several-year effort to understand the role of genetic variants in autism," says Gerald Fischbach, scientific director at the Simons Foundation, which funded the State and Wigler studies. "The microarray studies have shown beyond doubt that there are indeed rare genetic variants that account for a significant fraction of autism."

Among the studies' most tantalizing findings is the identification of a region of the human genome that appears to be connected with two disorders involving opposite social tendencies. Mutations that produce extra copies of this region, called 7q11.23, are associated with autism spectrum disorders, the State and Wigler teams report. Conversely, deletions of this region are known to be responsible for a disorder called Williams syndrome, which is characterized in part by a highly sociable, empathetic personality.

"This region of the genome could be a Rosetta Stone for studying the development of the social brain," State says.

In the new work, the two microarray studies found that the children with autism are about four times as likely as their unaffected siblings to have de novo 'copy number variants' (CNVs), mutations in which a region of the genome, sometimes as long as several million base pairs, is either duplicated or deleted. What's more, the research teams found that typically, the CNVs in the children with autism both are larger and contain a higher density of genes than the CNVs found in unaffected siblings.

The analyses identified a total of about 75 CNVs worthy of further study, including between 4 and 6 for which the groups feel that the evidence is quite strong. Based on their data, the researchers project that there are potentially several hundred different regions of the genome where a CNV can increase the risk of autism, meaning that the current findings represent "not even the tip of the iceberg," Wigler says.

Since the CNVs involved in autism are rare variants, most of the CNVs discovered by the two research groups appeared just once in the entire study population. A handful of CNVs, however, appeared in more than one individual. To assess the importance of these 'recurrent' CNVs, both teams developed rigorous approaches to evaluating their statistical significance. They found that the association of autism with region 7q11.23 was highly significant; even more significant was a region called 16p11.2. While CNVs at 16p11.2 had been eyed in previous studies as a possible autism risk factor, the region's relevance to autism is now established beyond doubt, both groups agree.

"This is a clear and convincing replication, and in this field that's a cause for real celebration," says Yale's Stephan Sanders, lead author of the multi-site study. "Once we know something with certainty from a genetic standpoint, that opens the door to a whole range of biological studies."


The mission of the Simons Foundation is to advance research in basic science and mathematics.

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