While variants are rare, they occur in pathways associated with neurological processes.
Researchers are implicating several new candidate genes and genomic variants as contributors to autism and note that many more remain to be discovered. While the gene alterations are individually very rare, they mostly appear to disrupt genes that play important functional roles in brain development and nerve signaling. While an association between genomic variants in certain nervous system processes and autism has been hypothesized in the past, the scientists believe that their work definitively links these biological functions to autism.
“This large study is the first to demonstrate a statistically significant connection between genomic variants in autism and both synaptic function and neurotransmission,” states Peter S. White, Ph.D., a molecular geneticist and director of the Center for Biomedical Informatics at The Children’s Hospital of Philadelphia.
“Prior genomic studies of autism have successfully identified several genes that appear to confer risk for autism, but each gene appears to contribute to only a small percentage of cases,” adds Xiaowu Gai, Ph.D. “Our approach considered whether groups of genes with common biological functions collectively accounted for a greater percentage of autism risk.” Dr. White was senior author and Dr. Gai was lead author on the study, which appears online in Molecular Psychiatry. The paper is titled “Rare structural variation of synapse and neurotransmission genes in autism.”
Dr. White’s team compared the DNA of more than 1,000 children with autism to control sets of healthy subjects. Findings were reinforced using information from mouse models, showing that mice with abnormal motor and learning behaviors similar to human autistic behaviors were more likely to have CNVs in genes analogous to human autism genes.
The investigators searched for CNVs in a discovery cohort of 631 children with autism, 1,162 parents of these children, and a healthy control set of 1,775 children. They found nearly 400 inherited CNVs in autism subjects that did not occur in controls. They also analyzed a second cohort of 593 additional autism subjects, 1,109 corresponding parents, and 2,026 healthy controls. From this they found another set of nearly 400 inherited CNVs exclusive to children with autism.
Surprisingly, no single gene was frequently disrupted in either set, and only a few genes harbored CNVs in both sets. Although there was relatively little overlap between sets of CNVs found in the two cohorts, the CNVs tended to occur in genes that affected biological processes relevant to autism.
“While individually, CNVs are rare, each of them often appearing only in one family in our study, we found in this study that CNVs tend to occur in genes with similar functional roles—most especially in affecting synapse function, neurotransmission, and brain development,” says Dr. White.
“This suggested to us that there may be many different—possibly even hundreds—genetic paths to autism, with only a few gene alterations relevant to each individual patient. But if those hundreds of genes have similar roles in the nervous system, the end result may lead to the same diagnosis: an autism spectrum disorder.”
With many genes possibly involved in autism, Dr. White continues, researchers face a stronger challenge in devising gene-based diagnostic tests and eventually developing drug treatments than would be the case if fewer genes were involved. However, the fact that the current study consistently pointed to the same functional pathways and gene sets associated with neurological processes strongly suggests these pathways could be fruitful targets for further investigation, he concludes.