October 8, 2009 – Three University of Utah Department of Psychiatry researchers are part of an international team of scientists that has identified a novel region of the human genome that may confer susceptibility to autism.
Using genome information from more than 1,000 families with multiple affected individuals, including more than 150 Utah families, the researchers discovered a region on chromosome 5 that was significantly associated with autism. Their finding highlights the importance of genetic variation in the development of autism, according to a study published Oct. 8, 2009, in Nature.
Autism is a neurodevelopmental disorder that leads to impaired social interaction, challenges with communication, repetitive behaviors, and restricted interests. Although autism is a heritable disorder with more than 90 percent heritability by twin and family studies, attempts to identify genes that increase susceptibility to autism have met with limited success.
“Autism and other autism spectrum disorders are complex diseases,” says William M. McMahon, M.D., professor and chairman of psychiatry at the University of Utah School of Medicine and a contributor to the study. “While previous research and familial studies have suggested that there are strong genetic components that predispose to autism, this study adds to accumulating evidence that multiple rare mutations, rather than a single mutation, contribute to autistic susceptibility.”
The scientists first studied 1,031 families, with a total of 1,553 children affected with autism, from the Autism Genetic Resource Exchange and U.S. National Institutes of Mental Health repositories. They discovered that variations in a region on chromosome 5 near a gene called semaphorin 5A (SEMA5A) were linked to the development of autism. SEMA5A is a gene that is thought to be involved in axonal guidance, the process by which nerve cells send out fibers to conduct electrical impulses.
“Earlier studies have shown that the expression of SEMA5A is lower in the peripheral blood of individuals with autism,” says Hilary Coon, Ph.D., also a co-author on the study and U of U professor of psychiatry. “It is reasonable to think that disruptions in genes involved in how axons in the brain find their correct targets might contribute to autism susceptibility, and this study provides additional evidence implicating SEMA5A.”
To confirm their findings, the researchers performed replication studies using data from the Autism Consortium, Autism Genome Project, and other autism family samples from around the world and Utah. They also compared brain bank tissue from 20 persons with autism to tissue from controls and found that expression of the SEMA5A gene was significantly lower in the brains of those with autism.
“It is worth noting that the genomewide significance of this region on chromosome 5 was only found when the results from the initial large set of families and the replication families were pooled in a meta-analysis,” says Coon. “Nevertheless, SEMA5A is an interesting candidate gene for autism susceptibility because it codes for a protein that is both attractive and inhibitory for developing neurons.”
The study authors also suggest that, based on their findings, there are likely to be multiple rare mutations leading to autism susceptibility and, even when the same gene may be involved in susceptibility across multiple people, there are likely to be differences in the exact mutations from one person to the next. In fact, additional evidence from this study suggests that common genetic variation with moderate to strong effects on the clinical manifestations of autism is unlikely to be found.
“This study really highlights the complexity of the genetics underlying autism,” says Coon. “We are grateful for the enormous effort given by thousands of autism families from around the world, and particularly for the continued involvement of our local families here in Utah. These international collaborations may provide the keys to unlocking the secrets of complex diseases such as autism.”
Judith S. Miller, Ph.D., U of U associate professor of psychiatry, also was a co-author on the study, which was funded in part by Autism Speaks. Additional support for the University of Utah Autism Research Project comes from the Utah Autism Foundation and from the National Institutes of Health.