ADHD with and without CNVs

As per previous posts on this blog, the shift from the 'one gene condition' hypothesis to that of a more 'lots and lots of genes involved probably with some variable environmental contribution' hypothesis in cases of autism and related conditions seems to have taken hold with some vigour over the last few years.  Lots of fancy acronyms like SNPs and CNVs, combined with words like pleiotropy and epigenetics, have sprung up accompanying our realisation that no matter what your diagnostic label or not, we are all seemingly a product of our various mutations and any interplay between our genes, our mutations, and environment is likely to be complex.

I say all this because of a recent article appearing by Langley and colleagues* which very interestingly looked at cases of attention-deficit hyperactivity disorder (ADHD), comparing those who carried various CNVs against those who didn't and finding, well, very little difference between the cases in terms of things like symptom presentation. Many of the authors on this paper are no stranger to ADHD research, looking at things like comorbidity of bipolar disorder and ADHD and also having some pretty outspoken views about what ADHD might be.

The paper is full-text so I won't start copying and pasting large parts of it, but will provide a short summary:

• Children/young adults (n=567) diagnosed with ADHD (or hyperkinetic disorder) were included for study. Participants were also screened for an autism spectrum condition and excluded from the dataset if autism was suspected.
• The sample was divided up into those with at least one large rare CNV (n=77) and those without (n=490) and compared on various measures.
• Those ADHD cases with CNV(s) presented more commonly with intellectual disability (ID) (IQ<70); although this finding was not mutually exclusive to the CNV group. No other measure or variable of early developmental history or symptom severity was significantly different between the CNV(s) and non-CNV(s) groups (maternal smoking during pregnancy being slightly higher in the CNV group wasn't that far off at p=0.07).

The authors report that this finding points to no presence of an 'atypical' group of children where ADHD is comorbid to CNVs. They also point to a few caveats based on things like sample sizes and power, whether CNVs were de novo or inherited and the 'scattergun' approach they used (looking at CNVs located at various different parts of the genome with various potential weightings in relation to symptom presentation). Bear also in mind that these participants were all white, British children, predominantantly male, and some carried other behavioural comorbidities, and therefore to what group/population the results are probably going to be most applicable to.

I agree with all this issues and tread cautiously as a result. One thing does however stick out from this work about CNVs and ADHD and the question of whether the presence of CNVs might be more related to intellectual disability (ID) rather than other presentations like ADHD or even autism spectrum conditions? Looking at the degree of significance (table 1), the ID difference was pretty stark between the groups (p=0.0001). I know, I know, I am compartmentalising and that is never a good idea (the whole being greater than the sum of its parts and all that). One possibility to answer this question would be to look at an independent sample of children (white, British) with and without ID, screening negative for ADHD and autism as per the same instruments used in the current study and see what the rates of similar CNVs are. The list of CNVs is available at the foot of this article as a supplementary PDF. Indeed how about a similar study comparing groups of children with autism with and without those CNVs (given the suggested overlap) and see if this illuminates the path any better?

* Langley K. et al. Clinical and cognitive characteristics of children with attention-deficit hyperactivity disorder, with and without copy number variants. Br J Psychiatry. November 2011.