Autism is a mental disorder characterized by behavioral problems that may include a lack of social and communications skills, such as failure to respond to one's own name, intense tantrums and general detachment. In the last decade the diagnosis of autism has increased 10-fold. It is now believed to affect one in 166 children born in the U.S. and four boys for every girl.
"Although we know autism is highly inheritable, complex gene interactions and submicroscopic anomalies create a din of statistical noise that drowns out detection of signals from linked sites in the genome," says study co-author Bernie Devlin, a human geneticist at the University of Pittsburgh. "To amplify these signals, we brought to bear gene chip technology with a huge sample, and also screened for these fine-level anomalies, factoring them into the analysis."
Using a DNA microarray, or gene chip, the team was able to scan large stretches of sequence for tiny deletions common within the study families. They also sought out copy number variations and large-scale insertions or deletions of genetic material. In the two-fold analysis, the researchers implicated the gene neurexin 1, located on chromosome 2, as well as a swath of sequence on chromosome 11.
Neurexin 1 is part of a three-member family of genes coding for proteins involved in communication between neurons. It is associated with glutamate, the neurotransmitter known to elevate neuronal activity and play a role in wiring the brain during early development. Glutamate functioning has been implicated in other syndromes involving mental retardation of which autism is often a symptom, such as fragile X syndrome and tuberous sclerosis. Neurexin 1 is specifically believed to be involved in building glutamate synapses, the links through which glutamate neurons send and receive electrical signals.
"Often you don't have any idea of what a gene does, but in this case we know neurexin 1 is involved at sites where the neurotransmitter glutamate is released," says study coauthor Gerard Schellenberg, a medical researcher at the University of Washington. "As for the chromosome 11 location, we think there is another susceptibility gene there and we are actively pursuing it. We are in the neighborhood and have a plan to find it. The section of chromosome 11 identified in the study has been linked to proteins that ferry glutamate across synapses.
Genetic anomalies, from tiny deletions or substitutions of single bases to large stretches of missing code or even multiple copies of the same code, often crop up in the human genome and, occasionally, can create a disposition to a particular type of disorder. Among the variations found in the Autism Genome Project subjects was the deletion of the neurexin 1 gene. Much of the autism research community believes there may be roughly six major genes involved in autism, and maybe 30 others that may confer some risk. A combination of mutations in any of these genes could contribute to the likelihood of being born with autism. Because a number of different genetic factors may contribute to this disease, identifying these markers is made very difficult and large sample sizes are needed to get significant results.
"These findings are a piece of the puzzle," says Geraldine Dawson, director of the University of Washington's Autism Center. "As we identify these genes we will be able to screen young children for autism at an early age and begin interventions earlier, which can have a dramatic effect for some children."
These results are the culmination of phase 1 of the Autism Genome Project, which began in 2002 with the sharing of samples and data from labs around the world. Phase 2 will follow up on the leads discovered in the first phase. The $14.5 million project will receive funding from various institutions such as the National Institutes of Health and Autism Speaks, an organization dedicated to increasing the awareness of and finding a cure for autism spectrum disorders.
"Autism is a very difficult condition for families—communication is taken for granted by parents of healthy children but is so greatly missed by those with autistic children," says study co-author, Jonathan Green, a child psychiatrist at the University of Manchester in England. "We hope that these exciting results may represent a step on the way to further new treatments in the future."