Tuesday, 1 March 2011

CNVs in autism

I have always found it a little hard going coming to grips with the various studies on the genetics of autism. Right from the early studies looking at the rates of autism in twins (whether monozygotic or dizygotic) through to the often complicated world of which genes may show linkage to autism, I would probably give myself a D+ (must try harder) in this area of understanding.

What I believe (I think) from the work so far is that: autism is an extremely heterogeneous condition with variable presentation, numerous co-morbidities and most probably a non-Mendelian form of inheritance. In English this means that people with autism are not the same as one another in how their symptoms present and unlike other conditions such cystic fibrosis, the genetic roots are not so easily traceable or identifiable.

In recent years, genetic research in autism has seemingly undergone something of a transformation in terms of what it could do, paralleling research in other areas. Gone are the days where one, two or three genes are implicated; to be replaced with an altogether complex model of variability, overlap and importantly gene-environment interactions (also others epigenetics, epistatis, pleiotropy). Probably without knowing it, readers of this blog will have already been exposed to gene-environment interaction research through my many and varied posts on coeliac disease.

One particular area of genetic research has come to the forefront in recent times - copy number variations (CNVs). OK you say, what on earth are CNVs? Well, the long and short of it is here, but in as few words as possible CNVs are the gains and losses in DNA sequences. Genetics lesson over (phew!). An article published today has caught the eye of quite a few people on the blogosphere in its conclusions regarding genetics and autism. The paper by Gai and colleagues was published in Molecular Psychiatry and happily is open access - a little bedtime reading anyone? There is quite a readable summary of the study on ScienceDaily.

What did it show? Well first of all is suggests that autism is a complex condition. No really, autism is highly complex when it comes to the identification and effects of genes on the condition. So complex in fact that there were just as many CNVs in their non-autism control group as there were in the autism group. What this suggests is that we all carry various deletions, insertions, etc in our DNA, whether we are autistic or not. Next finding: when, during this study, they attempted to test nearly 400 candidate CNVs initially identified in people with autism against another independent set of participants with autism, the grand total of overlap was 11.1%. In other words roughly 10 percent of CNVs from their first autism cohort were present in their second autism cohort. Man, that is complex.

Don't get me wrong, the overlapping CNVs they reported relating to areas such as synaptic transmission are important areas that require further study and replication. The take-home message has to be however that the genetic basis to autism is complicated and currently there are no consistent candidates which differentiate an autism diagnosis from a non-autism diagnosis (so far).

This is a good study - it had a decent initial sample size, control groups and importantly a second cohort of participants with autism to test their initial findings. Autism research could learn a lot from this kind of methodology. I do wonder whether such work is however fundamentally flawed. Not because of the wide heterogeneity present in their sample groups with autism but because of the logic that they are just comparing autism and non-autism; which they aren't. As we know, autism is a collection of symptoms moulded into a diagnostic label. Underneath autism are the same genetic nuances that we all have; our susceptibility to other diseases and conditions, our individual diversity in terms of physical characteristics (why is my nose this big?) and our intimate relationship with our environment (why did I get ill after that and he didn't?). Until we are able to definitively plot some deciding variable (or variables) which says that 'this is autism' and 'this is not-autism' outside of just presented behavior and developmental history, we are stuck with the influence of all these other variables biasing and modulating our findings.

I do wonder whether we will ever get to the point where we can answer questions on genetics and autism given the complexity of the whole thing; or indeed whether we should just accept that the genetic diversity in autism is the same as the genetic diversity in non-autism and look to more functional objectives.