Tuesday 22 July 2014

Common variation and the genetics of autism

The paper by Trent Gaugler and colleagues [1] reporting that the genetic architecture of the autism spectrum disorders (ASDs) seems in the most part to be due to "common variation" over and above "rare variants or spontaneous glitches" adds to the quite voluminous literature in this area.
Everything in proportion? @ Wikipedia 

Based on an analysis of "a unique epidemiological sample from Sweden" researchers looked at DNA variations in some 3000 individuals with autism and asymptomatic controls. They were able to model their findings "based mostly on combined effects of multiple genes and non-shared environmental factors" including some "synthesis of results from other studies".

Their results: "Most genetic risk for autism comes from common inherited gene variations that can be found in many individuals without the disorder" as per one write-up of the study results. Spontaneous mutations - those so-called de novo mutations which seem to be of growing interest to autism research - were reported to only 'modestly' increase risk of the condition (2.6% of the total risk). About 40% of the risk was unaccounted for, but combined with those common inherited gene variations, made up about 90% of the total risk or liability for ASD.

Quite a lot of the discussion about these results has focused on the issue of tiny genetic effects which many people not on the autism spectrum have present in their genome adding up into something with "substantial impact" when present together. Other research has hinted at similar things as for example, in the paper by St Pourcain and colleagues [2] looking at the genetics of social communication issues.

Whilst I do think that the Gaugler paper is an important one, I am minded to suggest a few words of caution. First and foremost is the reliance on observed genetic variation in the current paper. Although no expert in genetics, my very basic knowledge is that such variations are structural in nature as per issues like single-nucleotide polymorphisms (SNPs). The presence of such mutations (which we all have by the way, dotted around our genomic landscape) whilst of interest, don't actually though tell you an awful lot about the function of particular genes as a consequence of those point mutations unless further studies are conducted. Genes for example expressing protein can be affected by such mutations but, as we've come to realise in the past few decades, gene expression is also to some degree affected by other variables, as per the rise and rise of the science of epigenetics and the focus on non-structural effects on the genome. It's beyond the scope of this post to go too heavily into epigenetics and autism, but the research forays so far have provided some interesting data on issues like DNA methylation and autism (see here) and potential knock-on effects (see here). Importantly, structural variations might not necessarily be the same, or have the same effects, as epigenetic variations although the two may work synergistically.

Second, and I hate to bang on about this, but autism or ASD does not normally appear in some sort of diagnostic vacuum. As per the Gillberg work on the ESSENCE of autism (see here) or the 'big data' studies from the likes of Kohane and colleagues (see here), not only is autism an extremely heterogeneous condition in terms of presentation, but also a condition more than likely to co-exist alongside some heightened risk of certain comorbidity. It's all well and good saying that cumulative common genetic variants raise the risk of autism but, as per other biomarker discussions, we might very well replace the word autism with something like attention-deficit hyperactivity disorder (ADHD) or epilepsy or even something more somatic along the lines of the various work looking at autoimmune conditions appearing alongside autism. In short, genetic risk might be related to other things outside of just autism or its individual traits, and as I was reminded recently: "correlation is not the same as causation" (thanks Natasa). Oh, and then there is the RDoC initiative to consider...

Finally, it is a glaring omission in quite a bit of the coverage of this paper that the 41% of risk "unaccounted for" does not receive more interest than it has. I don't want to speculate on what might be included in the array of factors involved in this category (outside of my previous chatter on possible epigenetic factors) but will again draw your attention to other work on the old genetics-environment relationship with autism in mind and the question of heritability (see here and see here). That also one media piece talking about the Gaugler study is quoted as saying: "On their own, none of these common variants will have sufficient impact to cause autism" is an important detail which implies both cumulative effects and possibly the input of some external force(s). And those effects may very well cross the nature-nuture debate in some instances as per the results from Mitchell and colleagues talked about in a previous post.

Deciphering the genetic architecture of autism is still very much a work in progress. This latest contribution to the issue is important not least for the conclusions arrived at with talk of an additive model and it's intersection with common genetic mutations present in the general population. That being said, I still want to see more from the discipline. I'd like to see a more comprehensive analysis taking into account both genetic and epigenetic factors crossing environmental contributions too. I'd also like to see more focus on smaller groups on the autism spectrum as a function of things like developmental trajectory (see here) or response to certain interventions (see here). And for those who seem to be using this work as a hammer against environment being related to cases of autism, just remember, there may be many, many routes towards a clinical diagnosis...


[1] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

[2] St Pourcain B. et al. Common variation contributes to the genetic architecture of social communication traits. Mol Autism. 2013 Sep 18;4(1):34.


ResearchBlogging.org Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, & Buxbaum JD (2014). Most genetic risk for autism resides with common variation. Nature genetics PMID: 25038753

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