Autistic Brains 'Genes Differ'

The BBC say:

The brains of people with autism are chemically different to those without autism, according to researchers. A study, published in the journal Nature, showed the unique characters of the frontal and temporal lobes had disappeared.

It's not a bad summary, although it doesn't explain quite how interesting the new results are. Here's the paper, from a joint US/British team: Transcriptomic analysis of autistic brain reveals convergent molecular pathology

The authors took 19 brains from people with autism and 17 healthy ones. These came from people who donated their brains to science and then died. The study involved taking samples from three areas of the brain, the superior temporal gyrus, the prefrontal cortex, and the cerebellum. These are regions that have been implicated in autism, although to be honest, so has everywhere else in the brain.

They then looked at gene expression: mRNA levels. This measures the degree to which different genes are "activated" and being used to make proteins. Bear in mind that a gene itself could be completely normal, and yet be abnormally expressed: this was not a study of DNA mutations. So the BBC's headline is a bit misleading. The genes themselves were not the focus of this study.

Anyway, comparing the autistic and control brains, they found 444 genes that were statistically significantly either over- or under-expressed in the cerebral cortex samples from the autistic group. However, in the cerebellum, there were just 2 differences: so the cerebellum was ruled out from further analysis.

They then replicated the study in a different cortical area in 6 new cases and 5 new controls. They found extremely strong overlap with the original cohort, with the same genes being altered in the same direction in almost all cases. This makes me confident that there is something going on here. This scatterplot shows that almost all of the genes that were significantly different in the first batch were also different in same direction in the second one (although not always significantly, as you'd expect.)

However, the authors didn't stop there, and this is where it gets interesting. First, they used a pattern classification algorithm to try to distinguish patients and controls on the basis of gene expression. This is very much like the paper from last year showing that pattern classification could predict autism on the basis of brain structure.

Interestingly, the algorithm correctly " diagnosed" a case of autism who turned out to have a 15q duplication mutation. 15q duplication is a genetic disorder which causes autism, amongst other things, and it may explain up to 1% of cases of autism. This is only one case but it's important because it suggests that "15q autism" is not all that different to other kinds of autism on the neural level.

The authors then looked at what the over- and under- expressed genes actually were. They found that the "up" genes tended to be genes relating to immune and glial function, while the "down" genes tended to be involved in the formation and function of synapses between cells.

Very interestingly, one of the major clusters of genes , "M12", showed strong overlap with genes previously known to be expressed in a type of cell called PV+ GABA interneurons. In mouse models of autism, these are known to be deficient. M12 was underexpressed in autism, and it contains many genes which have previously been found to be mutated in some people with autism, such as CNTNAP2.

Another cluster, "M16", was overexpressed; it contains genes involved in immune and microglial function (microglia are specialized immune system cells inside the brain). However, M16 did not contain overrepresentation of suspected asd genes.

So this all points to something like this: autism is caused by disruption to the function of certain gene networks in the brain involved in synaptic function. This network is a delicate balance and it can be thrown off course by many different mutations and/or environmental factors.

There's no one gene for autism, but all of the genes for autism might be related, or rather, they might form a team that works together. If you want to look at it this way, you could say that autism is a bit like blindness. People can go blind for lots of different reasons: it could be damage to the surface of the eye, or the retina, or the optic nerve which carries information to the brain, or the brain itself. All of these parts depend on all the others to work, and if one of them goes wrong, the whole system suffers.

Also, whatever the abnormality in autism is, it seems to trigger a secondary change in the brain which is immune and/or glial related. By "secondary" I don't mean that it's less important. It might be what causes the symptoms of autism. But it's not the root cause (because if it were, mutations in this network would cause autism, and they don't seem to.)

This study raises many more questions than it answers, but in a good way. It certainly doesn't explain autism, but it's pointed the way towards more focussed research in the future - gene cluster M12.

Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe BJ, & Geschwind DH (2011). Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature PMID: 21614001