Genome-Wide study of autism published in Nature
Thursday, October 22, 2009

Combining family- and population-based approaches sheds new light on the potential roles of human genetic variation

In one of the first studies of its kind, an international team of researchers has uncovered a single-letter change in the genetic code that is associated with autism. The finding, published in the October 8 issue of the journal Nature, implicates a neuronal gene not previously tied to the disorder and, more broadly, underscores a role for common DNA variation. In addition, the new research highlights two other regions of the genome, which are likely to contain rare genetic differences that may also influence autism risk.

Modern approaches that harness genome-scale technologies have begun to yield some insights into autism and its genetic underpinnings. However, the relative importance of common genetic variants, which are generally present in the human population at a frequency of about 5 percent, as well as other forms of genetic variation, remains an unresolved question.

To more deeply probe autism's complex genetic architecture, a large multinational collaboration led by researchers at the Broad Institute of Harvard and MIT, Massachusetts General Hospital, Johns Hopkins University and elsewhere devised a two-pronged, genome-scale approach. The first component makes use of a family-based method (called "linkage") that analyzes DNA from autism patients and their family members to detect portions of the genome that harbor rare but high-impact DNA variants. The second harnesses a population-based method (known as "association") that examines DNA from unrelated individuals and can expose common genetic variants associated with autism that tend to exert more modest effects.

The researchers' results highlight three regions of the human genome. These include parts of chromosomes 6 and 20, the top-scoring regions to emerge from the family-based linkage studies. Although further research is needed localize the exact causal changes and genes within these regions that contribute to autism, these findings can help guide future work.

The other major result, this one flowing from the population-based analyses, is a single-letter change in the genetic code known as a single nucleotide polymorphism, or SNP (pronounced "snip"). This common variant lies on chromosome 5 near a gene known as semaphorin 5A, which is thought to help guide the growth of neurons and their long projections called axons. Notably, the activity or "expression" of this gene appears to be reduced in the brains of autism patients compared to those without the disorder.

Although the Nature paper identifies a handful of new genes and genomic regions, the researchers emphasize that the findings are just one piece of a very large -- and mostly unfinished -- puzzle. Future studies involving larger patient cohorts and higher resolution genomic technologies, such as next-generation DNA sequencing, promise to yield a deeper understanding of autism and its complex genetic roots.

Adapted from a Broad Institute press release.

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