Chromosomal deletions and ADHD

A study in the Lancet seemed to imply that large chromosomal deletions could cause ADHD - children with ADHD were found more often to have such deletions than control subjects. However there is a flaw in the argument because according to the paper the children with ADHD also had lower IQ than controls. It is already known that large chromosomal deletions are associated with intellectual impairment. So a plausible explanation is that by selecting children with ADHD one obtains a sample with low IQ and such subjects can be expected to have more large deletions by virtue of their lower intelligence rather because of any specific relationship between deletions and ADHD.

Of course, at one level it is true that ADHD is associated with large deletions. But if the effect is mediated by IQ then this is somewhat different from the notion that "deletions cause ADHD". To test this, one would need to study a sample of subjects with ADHD compared with controls who had been matched for IQ.



I did submit a letter to the Lancet pointing this out but unfortunately they have a strict policy of not considering letters submitted more than a couple of weeks after the article is published. So I've reproduced the letter below. Hopefully it's fairly self-explanatory.



Intellectual functioning confounds claim that CNVs are associated with ADHD



David Curtis



Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London E1 1BB. Tel +442073777729. Fax +442073777316. Email david.curtis@qmul.ac.uk



The claim that rare chromosomal deletions and duplications (copy number variants, CNVs) are associated with a diagnosis of ADHD (1) is unsubstantiated because the increase in CNV rate among subjects with ADHD may simply be due to an association between CNVs and low IQ. The study reports that there is a much increased rate of large CNVs among subjects who have ADHD and intellectual disability (IQ<70, one-tailed p=0.0002) but also a less highly significant increase among subjects with ADHD whose IQ falls within the normal range (IQ>=70, one-tailed p=0.0077). However this latter group has a mean IQ of only 89. If one takes a sample from the general population and then excludes those with IQ<70 one expects to see a mean IQ among the remainder of over 100. Thus it is clear that these ADHD subjects, while having an IQ which is not “below normal” still have an IQ which is “below average”. It is entirely plausible that the results are explained entirely by the fact that the ADHD subjects have below average IQ and that large CNVs occur more commonly in subjects with below average IQ, since it is already established that they are commoner in people with below normal IQ (2).



In order to demonstrate that CNVs conferred a specific risk of developing ADHD one would have to compare a sample of subjects with ADHD against a sample of IQ-matched controls. It is possible that similar caveats may apply to some extent to claims for the association of CNVs with schizophrenia and autism (3, 4), since excluding subjects with intellectual disability does not mean that one has necessarily fully eliminated intellectual functioning as a confounding factor.



1. Williams NM, Zaharieva I, Martin A, Langley K, Mantripragada K, Fossdal R, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet. 2010 Oct 23;376(9750):1401-8.

2. Mefford HC, Cooper GM, Zerr T, Smith JD, Baker C, Shafer N, et al. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome research. 2009 Sep;19(9):1579-85.

3. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008 Sep 11;455(7210):232-6.

4. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009 May 28;459(7246):569-73.