Gene variants in autism linked to brain development

New research on the genomics of autism confirms that the genetic roots of the disorder are highly complicated, but that common biological themes underlie this complexity. In the current study, researchers have implicated several new candidate genes and genomic variants as contributors to autism, and conclude 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 current research 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," said senior author Peter S. White, Ph.D., a molecular geneticist and director of the Center for Biomedical Informatics at The Children's Hospital of Philadelphia. Synapses are the contact points at which nerve cells communicate with other nerve cells, while neurotransmitters are the chemical messengers carrying those signals.

"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," said the lead author, Xiaowu Gai, Ph.D. "Our approach considered whether groups of genes with common biological functions collectively accounted for a greater percentage of autism risk."

The study appears online today in the journal Molecular Psychiatry.

White and colleagues compared the DNA of more than 1,000 children with autism to control sets of healthy subjects, searching for gene variants called copy number variations (CNVs) appearing in the genomes of autistic individuals and their families, but not in healthy controls. The study team reinforced their findings 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.

"Because the gene alterations that we found influence brain development, our hope is that they may eventually provide clues to developing diagnostic tests as well as treatments for children with autism," said co-author and lead clinician Josephine Elia, M.D., a child psychiatrist at Children's Hospital.

Unlike changes to single bases in DNA, called single-nucleotide polymorphisms (SNPs or "snips"), CNVs are larger alterations in DNA structure—missing or repeated stretches of dozens or hundreds of bases in sequence. CNVs have been implicated in other neuropsychiatric disorders, such as schizophrenia, bipolar disorder and attention-deficit hyperactivity disorder (ADHD)—the latter in a previous study by White and Elia.