Common genetic variants associated with autism

30 April 2009

Autism spectrum disorders (ASDs) are a group of related neurodevelopmental and neuropsychiatric disorders, including autism and Asperger’s syndrome, which become apparent in childhood and involve impaired verbal communication and social interaction along with repetitive behaviours. ASD has complex, multifactorial origins, but genetic factors are believed to be significant as the conditions show a high degree of heritability. A new paper in Nature reports the results of genome-wide association studies (GWAs) in more than 4300 affected individuals and their families, and almost 6500 controls, of European ancestry. The work was led by researchers from the University of Pennsylvania School of Medicine in the US, using DNA samples from the Autism Genetic Resource Exchange (see previous news).

The initial GWA study performed did not identify any variants as being significantly associated with ASD, nor did a series of further GWAs in independent data sets. However, combined analysis of the data revealed a single significant association with a single-nucleotide polymorphism (SNP) on chromosome 5. Five further SNPs from the same 5p14.1 region showed possible association, although this was not statistically significant. The region on chromosome 5 where the key variant was located is between two genes encoding neuronal cell-adhesion molecules cadherin 10 and 9 (CDH10 and CDH9) [Wang K et al. (2009) Nature doi:10.1038]. These cadherins are part of a group of molecules known to be involved not only in cellular adhesion in the brain, but also in the generation of synaptic complexity in the developing brain.

Although none of the SNPs identified in this study as potentially linked with ASD showed any association with expression levels of the cadherin 9 or 10 proteins, the authors postulate that elements in this region of the genome might regulate gene expression in the developing brain; physiological research has previously suggested that abnormal brain development (specifically, a lack or normal connectivity between neurons) may underlie ASD. The authors therefore propose that the genetic variants identified by their GWA study could indicate a genetic link to the underlying pathology of autism and related conditions, increasing the risk of ASD by affecting the normal expression of key cadherin proteins.

A second publication in Annals of Human Genetics also reports a link between ASD and genetic variation near the CDH10 and CHD9 genes [Ma D et al. (2009) Ann. Hum. Gen. 73 (3) 263-273]. An additional publication in Nature will reportedly present results identifying gene duplications and deletions more common among individuals affected with ASD, including further cell adhesion molecule genes and some involved with the ubiquitin system that may regulate turnover of cell adhesion molecules (see NIH press release).

Comment: Earlier research has linked rare genetic variants with ASD, particularly copy number and structural variants (see previous news), and suggested that the genetic contributions to both sporadic and apparently inherited forms of autism and related conditions are highly complex (see previous news). This latest research is the first example of common genetic variants to be associated with increased susceptibility to ASD. The authors correctly observe that their findings are merely “part of a larger effort to interrogate the complex genetic architecture of ASDs”. Lead researcher Dr Hakon Hakonarson was careful to underline this fact, saying: "There are going to be many genes involved in causing autism…In most cases, it's likely that each gene contributes a small amount of risk, and interacts with other genes and environmental factors to trigger the onset of disease" (see BBC news).

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