Autism is a genetic disorder. We've known this ever since the 1970s when studies by Susan Folstein and Michael Rutter showed that genetically identical twins are much more likely to both be autistic than non-identical twins. These findings were incredibly important at the time and fundamentally changed the way people think about autism. But they didn't tell us which genes cause autism or, perhaps more importantly, how they do it.
I've just been attending the Autism Brain Research meeting in San Diego. Much of the first day was dedicated to genetic research and animal models of autism. The gist of the talks was that, while there are some genetic variations that carry a high risk for autism, these are probably very rare and only account for a very small proportion of cases. Most 'genes for autism' will actually carry a very low risk of the person actually having autism, so identifying these genes is going to be difficult. However, a recent study, just out in Science Translational Medicine, offers a new perspective.
Ashley Scott-Van Zeeland and colleagues focused on one particular gene - CNTNAP2 - apparently referred to colloquially as the "catnap" gene. Previous studies have linked CNTNAP2 to autism, but also to specific language impairment, ADHD, Tourette syndrome, and schizophrenia. It encodes a protein, Caspr2, which is thought to be involved in the migration of cells during brain development and is expressed in frontal and temporal lobes in humans.
In the first part of the study, the authors conducted a genetic test on the saliva of 32 children, half of whom had a diagnosis of autism. Across the whole sample, they identified 9 kids who carried the allele (variant) of the CNTNAP2 gene that has been linked to autism. It's not clear how many of the 9 'at risk' kids were in the autism group, but reading between the lines it seems like a 5:4 split. Then, rather than comparing the autism group to the non-autism group, they compared the 9 children with the 'risk allele' to the remaining 23 children
fMRI was used to record brain activity while participants completed a reward-guided implicit learning task in which they were given a monetary reward for correct responses.
The first main finding was that the 'non-risk' group showed reduced activity in the medial prefrontal cortex (MPFC). This might sound a bit counter-intuitive, but the MPFC is part of what is termed the 'default mode network' - a collection of brain regions that show reduced rather than increased activity during cognitive tasks. So the risk allele was associated with a reduction in normal reduction in MPFC activity. If that makes sense. Previous studies have reported abnormal patterns of MPFC activity in autism during theory of mind tasks, as well as abnormalities of the default mode network. So this finding fits nicely with the autism research, except for the fact that it's looking at the CNTNAP2 gene, irrespective of autism diagnosis.
The authors also conducted connectivity analysis on residual time series. Put simply, this involved subtracting out activity related to actually completing the task and then looking at which brain regions showed a similar pattern of changes in activity over time as the MPFC. Individuals with the risk allele showed greater connectivity between the MPFC and neighbouring right frontal cortex, but reduced connectivity with more distant regions including the medial occipital cortex and the lateral temporal cortices*. This fits in nicely with the idea that "the frontal cortex in autism might be only talking to itself". Except again this a study relating to a risk allele, not to autism per se.
Just to be sure, the authors then analysed the data from a second study, using a completely different task and a completely different group of subjects. This time none of the subjects were autistic. But the connectivity analysis showed a very similar pattern of results. Individuals with the risk allele showed stronger local connectivity and weaker long-range connectivity with the MPFC.
So really, this study isn't about autism. It's showing a link between a gene associated with autism (CNTNAP2) and individual differences in patterns of brain activity that have been associated with autism. Having this gene doesn't mean that you've got autism. It doesn't even mean there's a high risk of autism. But it may have a subtle effect on the way the brain is wired up and this may put you at an ever-so-slightly higher risk of having autism. Or schizophrenia. Or language difficulties. Presumably, all depending on a host of other genetic and environmental risk factors to which you're also exposed.
One thing I'd really like to know is whether non-autistic individuals with the 'risky' variant of the CNTNAP2 gene differ in terms of their behaviour or cognitive processes. Are there subtle differences, for example, in language or perceptual processing, or their social characteristics? Or are they only observable at the brain level? Looking at this might help us work out which particular aspects of autism might be linked to this neural/genetic pathway.
* The authors also reported that the non-risk group showed focal patterns of connectivity between the MPFC and regions in the left hemisphere classically associated with language processing, including left inferior frontal gyrus, insula, anterior temporal pole, superior temporal gyrus, and angular gyrus. In contrast, the at-risk group showed much more widespread connectivity across both left and right hemispheres. However, while tantalising, it doesn't appear that these differences were statistically significant when direct comparisons were made between the two groups.
- Virginia Hughes (as per usual) had the scoop on this research last year.
- Discover and Time also covered the study
- Lindsay at Autist's corner has recently written about the CNTNAP2 gene and has covered some other autism genetics stories here and here
Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, Sonnenblick LI, Rudie JD, Ghahremani D, Mumford JA, Poldrack RA, Dapretto M, Geschwind DH, & Bookheimer SY (2010). Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2. Science translational medicine, 2 (56) PMID: 21048216