Advances in technology and analytical methods over the past several years have enabled a better understanding of genetic risk factors for ASD. The human genome has over 6 billion DNA nucleotides. Until recently, it has been extremely difficult for scientists to compare two groups of individuals – one affected by a condition versus a comparison group – in terms of their detailed DNA because such comparisons require the analysis of at least half a million to a million individual locations in the genome of thousands of people. New methods, called Genome-Wide Association Studies (GWAS), have now made it possible to perform such comparisons and identify single changes in DNA nucleotides as specific genetic risk factors. Although this powerful technology has already produced exciting findings in other complex diseases, it wasn't until 2009 that GWAS studies finally began to bear fruit for autism. In the Spring and again in the Fall, researchers reported successful application of GWAS technology to ASD.
GWAS is a powerful analysis technique that allows researchers to sift through hundreds of million of bits of genetic data to identify changes to the genetic code that are associated with a disease. Because the approach is not based on any specific biological hypothesis, scientists can cast the broadest experimental net possible, and use sophisticated statistical methods to establish the disease association. In recent years, GWAS has been successful in identifying susceptibility genes for such diverse conditions as macular degeneration, diabetes, rheumatoid arthritis, Crohn's disease, and bipolar disorder. In April 2009, a large team of scientists led by investigators at Children's Hospital of Philadelphia, reported results from the first successful GWAS study in autism1. Tens of thousands of DNA samples are required for GWAS to produce meaningful results, so working with collaborators that included members of the Autism Genome Project, the researchers pooled samples from the Autism Speaks-funded Autism Genetic Resource Exchange (AGRE) combined with many other collections. The result was identification of a DNA variant associated with the genes cadherin 10 and 9, which are responsible for creating molecules that facilitate the formation of neuronal connectivity. This finding is consistent with accumulating evidence suggesting abnormal interactions between neurons may be at the core of the deficits seen in autism [See 2008 Autism as a Synaptic Disorder and also 2009 Studies of Genetic Copy Number Variations].
The idea that faulty connections between neurons plays a major role in ASD was further supported with the publication of the second autism GWAS study in October2. Also working with AGRE and members of the Autism Speaks-funded Autism Genome Project, a collaboration led by investigators from Boston's Autism Consortium and Johns Hopkins University used a very different statistical approach to discover an association between ASD and the gene semaphorin-5A. Similar to the cadherins identified in the first study, semaphorin 5A is thought to play an important role in neural development.
Taken together, these two groundbreaking studies confirm the potential for GWAS to make successful contributions to our understanding of autism genetics. Remarkably, out of the approximately 20,000 different human genes the experiments could have identified, the genetic variations that were uncovered are genes involved in brain development, serving to expand and reinforce our current thinking about biological mechanisms of autism. Like all new findings, they continue to focus the attention of the scientific community on the next directions for research and exploration.