Monday, 12 December 2011

Genes, SNPs, CNVs and autism

I open this post with a quote from a relatively new article:

"We show that as many as 2193 genes, 2806 SNPs/VNTRs, 4544 copy number variations (CNVs) and 158 linkage regions have been associated with ASD by GWAS, genome-wide CNV studies, linkage analyses, low-scale genetic association studies, expression profiling and other low-scale experimental studies".

The paper in question is this one (open-access) from Li-Ming Xu and colleagues*.

The first thing that struck me when I read this abstract is wow... autism is complicated. OK, nothing new in that statement and for those regular readers who quite often see me gently tugging at the loose threads of various genetic findings, I suppose summaries like this go to show that the concept of an 'autism gene' is pretty well past distant memory seemingly heading the same direction as Voyager 1. In fact reading through this quite complicated paper, perhaps too complicated for me, several things popped into my mind. Stop me if you heard these before:

  • If there was a prize for really knuckling down, collecting and collating data, Li-Ming Xu and colleagues might very well be in the running for it. I say this not only for their paper but also the database they developed on the genetic findings related to autism which is quite brilliant (here). If you have a few hours free (don't we all!), I would definitely recommend browsing the dataset which covers everything including population differences, gender differences and even how the diagnosis of autism was arrived at.
  • Yep, lots of genetic findings related to lots of different autisms. When you see the the various studies all laid out and summarised like this, I tend to wonder what similar analyses might look like for other developmental conditions like ADHD, dyslexia, learning disability, etc. How about if researchers conducted genome wide analyses of a group of children randomly selected from your average town or city, how would they compare with these results? How much overlap would there be and how many genes might be associated with this random group? I would wager that there would be quite a bit of overlap in terms of the number of genes, SNPs, CNVs et al related to our random group simply because we are all the product of mutation.
  • Heterogeneity is something most people with a connection to autism will know about. If you've met one person with autism, you've met one person with autism is a common saying. Further complicating that heterogeneity is the issue of comorbidity; so like everyone else, people with autism carry varying risks for other conditions. Whether these conditions are more or less likely to be related to some of the collected genetic findings... [fill in the blank].
  • Given the wide range of genetic findings in "autism", is this perhaps a sign that the field of genetics needs to start (continue) diversifying; looking at sub-groups or phenotypes for example, a little more closely if it wishes to more ably describe autism or at least certain types of autism. There are already some signs of this happening as exemplified by the paper a few years back looking at paraoxonase gene SNPs in Italian vs. US cohorts.
  • As per previous posts, there is a new sheriff coming to town with regards to genetics; epigenetics: changes to gene function not due to changes to DNA. "Hey Pilgrim, you forgot your pop-gun".

Still today some people talk about an autism gene as if right on chromosome X [fill in the blank], findings are going to emerge to say that 100% of people with autism will show issues with gene X compared with 0% of the non-autism population (however you define this as) and that genetic tests for autism are only years away. The problem is that there is no evidence of this either happening now or going to happen any time soon. Indeed as with everything, the more you look at it, the more complicated technology you apply to it, the less you seem to know about it and the more questions start to be asked. Yes, our genes are a big part of us and control lots and lots and lots of different things. But they don't do it in isolation. Crikey, even our gut bacteria might be involved in some processes!

To end a song for Mrs Robinson.

* Li-Ming Xu. et al. AutismKB: an evidence-based knowledge base of autism genetics. Nucleic Acids Research. December 2011.