A research team has connected more of the intricate pieces of the autism puzzle, with two studies that identify genes with important contributions to the disorder.
One study pinpoints a gene region that may account for as many as 15 percent of autism cases, while another study identifies missing or duplicated stretches of DNA along two crucial gene pathways. Significantly, both studies detected genes implicated in the development of brain circuitry in early childhood.
"Because other autism researchers have made intriguing suggestions that autism arises from abnormal connections among brain cells during early development, it is very compelling to find evidence that mutations in genes involved in brain interconnections increase a child's risk of autism," said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia. He is on the faculty of the University of Pennsylvania School of Medicine, as is his main collaborator, neuroscientist Gerard D. Schellenberg, Ph.D.
"This comprehensive research opens the door to more focused investigations into the causes of autism disorders," said Philip R. Johnson, M.D., chief scientific officer at The Children's Hospital of Philadelphia. "It moves the field of autism research significantly ahead, similar to the way oncology research progressed a few decades ago with the discovery of specific genes that give rise to cancers. Our extensive pediatric genomics program has pinpointed particular genes and biological pathways, and this discovery provides a starting point for translating biological knowledge into future autism treatments." The hospital's Center for Applied Genomics, launched in 2006, is the world's largest facility dedicated to the genetic analysis of childhood diseases.
Collaborating with researchers from more than a dozen institutions, including members of the Autism Genome Project (AGP), Hakonarson led both studies, which appear today in online publication in Nature.
Autism is the best known of the autism spectrum disorders (ASDs), a group of childhood neurodevelopmental disorders that cause impairments in verbal communication, social interaction and behavior. Currently estimated to affect as many as one in 150 U.S. children, ASDs are known from family studies to be strongly influenced by genetics. Previous studies have implicated several chromosome regions harboring rare variants in raising the risk of ASDs, but until now, research has not been consistent in identifying and replicating common genetic variants.
One of the two studies by Hakonarson's team is the first to identify common genetic variants associated with autism. By using highly automated genotyping tools that scan the entire genome of thousands of individuals, the researchers found that children with ASDs were more likely than healthy controls to have gene variants on a particular region of chromosome 5. That region is located between two genes, cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry codes to produce neuronal cell-adhesion molecules.
Neuronal cell-adhesion molecules are important because they affect how nerve cells communicate with each other, thought to be an underlying problem in ASDs. "These molecules are expressed on the cell surfaces of neurons, and they are involved with shaping both the physical structure of the developing brain and the functional connections among different brain regions," Hakonarson said. "Although a particular gene variant may contribute a small risk for an ASD in a particular individual, we estimate that the variants we discovered may contribute to as many as 15 percent of ASD cases in a population - typically referred to as the population-attributed risk of the variant."
Hakonarson's team first performed genome-wide association studies on DNA from over 3,100 subjects from 780 families of children affected with ASDs, then performed further studies in a cohort of 1,200 affected subjects and 6,500 unaffected controls. They then replicated their results in two additional independent cohorts. In total, they analyzed DNA from 12,834 subjects.
"Autism Speaks is pleased to have facilitated this critical research, having provided both funding and access to thousands of DNA samples through Autism Speaks' Autism Genome Research Exchange (AGRE)," said Geraldine Dawson, Ph.D., Chief Science Officer for Autism Speaks. "Access to biomaterials and clinical data from thousands of families through the AGRE substantially expedites the research our community seeks and needs. Our goal is to accelerate genetic research that can ultimately lead to improved detection and medical treatments." Dawson also is a co-author of both studies in her role as a faculty member of the University of Washington.