Team finds excess of large CNVs, some of which overlap with loci for schizophrenia and autism.
An international team of scientists report what they claim is the first direct evidence that attention-deficit hyperactivity disorder (ADHD) has a tangible genetic component and is not purely a “social construct” attributable to poor parenting or bad diet. The team, led by researchers at Cardiff University’s MRC Centre in Neuropsychiatric Genetics and Genomics, and the department of psychological medicine and neurology at Cardiff University School of Medicine, identified a highly significant excess of large, rare copy number variants (CNVs) in children with ADHD compared with control participants.
Overall, the average number of CNVs per child with ADHD was 2.09 times higher than in controls, and both deletions and additions were evident, report Anita Thapar, M.D., and colleagues. Their results are published in today’s early online issue of The Lancet in a paper titled “Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis.”
ADHD affects about 2% of children, and most of those diagnosed continue to show impairment in adult life, Dr. Thapar and colleagues report. Although the condition is evidently highly heritable, no specific susceptibility genes have yet been unequivocally identified, and there is a persistent undercurrent of opinion that the disorder is mainly related to upbringing, they note.
Large, rare CNVs have, however, been found to contribute to neurodevelopmental disorders including intellectual disability, schizophrenia, and autism. To investigate whether such genetic deletions and additions could also be linked with ADHD, the authors carried out a genome-wide analysis of CNVs in 366 U.K. children with ADHD but without schizophrenia or autism and in another 1,047 matched controls. They then replicated their results from an independent dataset of 825 Icelandic patients with ADHD from deCODE Genetics.
“Our first aim was to examine whether children with ADHD had an increased burden of CNVs compared with controls and to test whether this increase was attributable to associated intellectual disability since ADHD, similarly to autism and schizophrenia, occurs with increased frequency in individuals with intellectual disability,” they explain. “Our second aim was to investigate whether identified CNVs in our ADHD sample were significantly enriched for a specific chromosomal locus or loci previously implicated in autism and schizophrenia.”
The results showed that 14% of ADHD children carried a CNV larger than 500 kb, compared with 7% of controls. Moreover, the enrichment of large, rare CNVs was greatest in the children with ADHD and intellectual disability. In this group of patients the average number of CNVs per patient was 5.69 times higher than in the control group. More specifically, 12 (36%) children with ADHD and intellectual disability carried a CNV larger than 500 kb compared with 38 (11%) of those without intellectual disability.
In addition to generating a concrete link between CNV burden and ADHD, the latest study also provides initial evidence that some of the CNVs in children with ADHD but not intellectual disability overlap with CNVs previously implicated in either autism or schizophrenia. “Eight of 40 CNVs larger than 500 kb identified in the ADHD group overlapped with a locus previously implicated in autism compared with only one of 78 in controls,” the authors report. “Our results suggest that there could also be a shared biological basis to these two childhood-onset disorders.”
The researchers similarly found that of the CNVs identified in ADHD, nine overlapped with a locus previously implicated in schizophrenia and other major psychiatric disorders. “Locus-specific tests revealed that this finding was largely due to the 16p13.11 region where we identified six duplications in participants with ADHD,” they explain. “In view of the strong evidence for association between duplications at 16p13.11 and schizophrenia, 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.”
There has been one previously reported investigation of CNVs in ADHD, and this didn’t throw up any promising genetic link with the disorder, the authors note. However, the previous study looked at CNVs of all sizes, rather than large CNVs, “which are the ones that are most likely to be deleterious and are particularly enriched in neurodevelopmental disorders such as schizophrenia,” they stress.
The Cardiff team hopes the findings will help overcome the stigma associated with ADHD, Dr. Thapar stresses. “Now we can say with confidence that ADHD is a genetic disease and that the brains of children with this condition develop differently to those of other children. In the future these findings will help unravel the biological basis of ADHD, which in turn will help in developing new and more effective treatments.”
