Using a well characterised sample, we show that children with ADHD have a significantly increased burden of large, rare CNVs that include both duplications and deletions. Importantly, since CNV burden is increased in people with unexplained intellectual disability, autism, and schizophrenia, our clinical assessment procedure allowed us to conclude that the CNV burden is not attributable to comorbidity with these disorders. Although ADHD is one of the most heritable psychiatric disorders, with a heritability estimate of 76%,1,2
genome-wide association and linkage studies have so far failed to identify common genetic risk variants. Our results suggest that further investigation of rare CNVs in ADHD is likely to be fruitful. Up to now, there has been only one reported investigation of CNVs in ADHD, which did not detect a significantly increased burden of rare CNVs in 335 patients with the disorder.12
However, that study examined CNVs of all sizes rather than large CNVs, which are the ones that are most likely to be deleterious24
and are particularly enriched in neurodevelopmental disorders such as schizophrenia.9–11
We also showed that large, rare CNVs identified in our ADHD cohort were significantly enriched for chromosomal loci previously implicated in autism and schizophrenia. ADHD is currently thought to be entirely separate from these disorders. However, there is some overlap between ADHD and autism in terms of clinical symptoms and cognitive deficits.33
Autistic traits and ADHD behaviours in the general population (not clinical disorder) also seem to be affected by shared heritability.34
Our results suggest that there could also be a shared biological basis to these two childhood-onset disorders. So far, possibly because of the dearth of relevant studies, there are no clinical or genetic data clearly pointing to overlap between ADHD and schizophrenia. In view of the strong evidence for association between duplications at 16p13.11 and schizophrenia,22
we note with particular interest that our ADHD cohort was significantly enriched for duplications at the same locus, a finding that was independently replicated in the Icelandic population. Moreover, further analysis of two duplications at 16p13.11 revealed that one was de novo, adding further support that this locus is functionally relevant to ADHD. Future studies analysing the segregation patterns of familial CNVs will be needed to estimate disease penetrance.
The consensus duplicated region at 16p13.11 spans only seven genes and is flanked by segmental duplications that predispose to recurrent chromosomal rearrangements (). The genes mapping within 16p13.11 therefore provide a specific focus for further research into the neurobiology of ADHD. Among the genes spanned by the CNV, NDE1
(nuclear distribution gene E homologue 1) is of particular interest because of its role in neurodevelopment and interaction with DISC1
(disrupted in schizophrenia 1), a gene implicated in schizophrenia and other major psychiatric disorders that encodes a protein also involved in neurodevelopmental processes.35,36
Other investigators have detected CNVs spanning this region; deletions have been strongly associated with intellectual disability,17,37
whereas duplications have been detected in patients with autism,38
again suggesting that the same large, rare CNVs might contribute to several, phenotypically different neurodevelopmental disorders.
Our findings have important clinical and research implications. First, our results emphasise that further investigation of CNVs in ADHD is a priority for research into this disorder. We do not suggest, however, that the search for common genetic variants using SNPs should be abandoned because, up to now, SNP-based studies1
have not had sufficient power to allow realistic assessment of the role of that class of variant in ADHD. Moreover, with the application of appropriate precautions such as we have undertaken, studies analysing SNPs and large, rare CNVs can be undertaken simultaneously. Key measures that allowed us to undertake such an analysis despite the use of two different SNP arrays were: that we limited our analysis to SNPs overlapping between platforms, we undertook quality-control checks in samples genotyped with both platforms, we validated the CNVs with independent platforms, and crucially, as our own cross-platform validation data show, we focused on CNVs large enough to be detected at high sensitivity and specificity irrespective of SNP array.
Second, the findings allow us to refute the hypothesis that ADHD is purely a social construct, which has important clinical and social implications for affected children and their families. Finally, although the number of children with intellectual disability in our sample is small, more than a third carried a large, rare CNV. None of these participants had been assessed for this type of mutation by clinical services. Microarray-based comp-arative genomic hybridisation enables the accurate detection of submicroscopic CNVs and is increasingly being used to investigate patients with intellectual disability or congenital abnormalities in some clinical settings. Our results suggest that routine referral to clinical geneticists and screening for such mutations could be helpful for children with ADHD and intellectual disability.