5/01/2009 - A multi-center team, including investigators in Vanderbilt’s Center for Human Genetics Research, has identified the first common genetic variation associated with autism.
The findings, reported in Nature and in the Annals of Human Genetics, point to a particular spot in the genome that may increase a person’s risk for the neurodevelopmental disorder and suggest the involvement of molecules that form connections between brain cells.
Autism is characterized by impaired verbal communication and social interaction, and by restricted and repetitive patterns of interest or behavior. It is part of a spectrum of disorders (ASD) that can range from relatively mild to quite severe and affect as many as one in 150 children in the United States, about three-quarters of them boys.
Evidence from twin and sibling studies has demonstrated that autism has a strong genetic component, but despite many attempts to find genetic risk factors, “there is no consensus on the underlying genetic architecture of the disorder,” said Jonathan Haines, Ph.D., director of the Vanderbilt Center for Human Genetics Research (CHGR) and a co-author of both studies.
Haines and longtime collaborator Margaret Pericak-Vance, Ph.D., director of the Miami Institute for Human Genomics at the University of Miami, conducted a genome-wide association study (GWAS) to search for common genetic variation that increases susceptibility for ASD. Common genetic variants are spots in the genome where a variable letter of the DNA code – called an SNP (single nucleotide polymorphism) – is present in at least 5 percent of the population.
The researchers examined 1 million SNPs in a discovery dataset that included 1,390 individuals from 438 autistic Caucasian families. They identified 96 SNPs as being strongly associated with autism risk. Using an independent validation dataset of 2,390 individuals from 457 autistic families, and analysis of 550,000 genetic markers, the investigators narrowed the list of potential autism risk SNPs. Two of the top 96 SNPs resided in a region on chromosome 5p14.1, which the researchers examined more closely, finding eight SNPs that associated with autism in this region.
Investigators at the Children’s Hospital of Philadelphia performed a GWAS on two additional datasets (one 780 family-based group and one case-control group with 1,204 cases and 6,491 controls). James Sutcliffe, Ph.D., a CHGR investigator and co-author of the Nature paper, provided additional Vanderbilt samples to the Philadelphia group.
That analysis also identified the 5p14.1 chromosomal region as containing common genetic variants associated with ASD.
“A complication of GWAS – where you’re analyzing between 500,000 and a million SNPs – is how to figure out which of the thousands of SNPs that look pretty good in the analysis are actually real,” Haines said. “That’s where having multiple datasets where the same thing shows up over and over again makes us confident about the result.”
Even though the findings support the notion that common genetic variation is important in autism susceptibility, the 5p14.1 region “explains only a small portion – probably less than 1 percent – of what we think is the genetic component of autism,” Haines said. “This clearly does not explain all of the genetics of autism, but we’re starting to put together at least part of the puzzle.”
The findings do point to a molecular pathway that may play a role in the development of the disorder, he noted.
The 5p14.1 locus lies between two genes that encode neuronal cadherins – cell-adhesion proteins that bind neurons together and are thought to be important for establishing cell connections during brain development. Additional analysis supported the hypothesis that cell-adhesion molecules – as a family – may be collectively associated with ASD. Variations in these molecules could cause changes to the brain’s functional connections and lead to the clinical symptoms of ASD.
“We are starting to see genetic pathways in ASD that make sense,” Pericak-Vance said.
A companion study in Nature offers additional support for a role for cell adhesion proteins in ASD. The authors of this study, including Sutcliffe, searched for genes that were duplicated or deleted in individuals with ASD. In the rare cases where such variations occurred, many tended to affect genes involved in cell adhesion.
It’s time to move beyond GWAS to understand the genetics of autism, Haines said. “It’s clearly not just common genetic variation that’s important.”
Because GWAS is tuned to find common variants, it misses genetic variants that occur in less than 5 percent of the population.
“Those sorts of variants are falling through the cracks right now,” he said. “Eventually we’ll be able to sequence everyone and figure this out.”
In the meantime, the Autism Genome Project, an international consortium that includes the Vanderbilt investigators, is conducting a GWAS on the largest dataset assembled to date (it includes the datasets from the current studies).
“That will effectively be the definitive analysis for common autism susceptibility variants,” Haines said.
The National Institutes of Health supported the research.©2013 Vanderbilt University Medical Center