In people with autism spectrum disorders, nerve cells in the prefrontal cortex and other brain regions show subtle defects. Rare genetic mutations account for only about 10 percent of autism cases. The cause of the remaining 90 percent remains unknown. Brain & Behavior Research Foundation Scientific Council Member Schahram Akbarian, M.D., Ph.D., and colleagues at the University of Massachusetts and the University of Maryland have now shown that epigenetic changes may play an important role.

Epigenetics refers to events that affect how genes are expressed without actually altering DNA structure. Dr. Akbarian, a 2000 NARSAD Young Investigator Grantee and professor of psychiatry and director of the Irving S. and Betty Brudnick Neuropsychiatric Research Institute at the University of Massachusetts Medical School studies epigenetics in relation to brain function and disease.

Of the new finding, reported in a paper titled “Epigenetic Signatures of Autism” in the Nov. 7, 2011 online edition of Archives of General Psychiatry, Dr. Akbarian states: “It’s been hypothesized that an epigenetic model of autism could potentially explain why genetic screening strategies for the disorder have been so difficult and frustrating. Our study is the first clear evidence gained exclusively from nerve cells pointing to a link between epigenetic changes and known genetic risk sites for autism.”

Within a cell, chromatin is the packaging material, made up mostly of proteins called histones, that keeps DNA bundled inside the nucleus. When DNA is inactive, it is tightly spooled around histones. Methylation is a process by which chemicals of the methyl group attach to a substrate to influence its activity. The study by Dr. Akbarian and his team was prompted by the hypothesis, as explained in their paper, “that epigenetic dysregulation of DNA methylation and histone modifications could play a prominent role in the pathology of autism and related disease.”

The researchers developed a novel method for extracting chromatin from the postmortem prefrontal cortex neurons of people who had been diagnosed with autism spectrum disorder and compared these samples with 16 normal control samples. They found hundreds of sites along the genome affected by an alteration in histone methylation in the brain tissue from the autistic individuals. The authors estimate that less than 5 percent of the affected genes they observed were directly the result of a mutation to the DNA, thus indicating epigenetic changes.

Being able to see the structural changes of the disorder on the molecular level offers understanding that can eventually lead to new treatments. As Dr. Akbarian explains: "Our understanding of psychiatric disorders, such as autism, is burdened by the fact that we often can't see the structural changes that lead to disease. It’s only by studying these diseases on the molecular level that scientists can begin to get a handle on how they work and understand how to treat them. Our study provides a starting point to construct, on a genome-wide scale, an ‘epigenetic risk map’ for autism. Superimposing epigenetic and genetic risk maps could greatly aid the understanding of individual cases and could be helpful in the design of more effective, individualized therapies and personalized medicine to treat the disorder.”