ADHD genes only part of the story

“The first direct evidence of a genetic link to attention deficit hyperactivity disorder has been found,” reported BBC News.

The research behind this news compared the DNA of 366 children with attention deficit hyperactivity disorder (ADHD) and 1,047 control subjects not known to have the condition. It found that 14% of children with ADHD had large, rare variations in their DNA that were present in only 7% controls.

Although this has been called "the first direct evidence" that ADHD is a genetic disorder, results from other genetic research and studies in twins have already highlighted the role that genetics play in ADHD. More research is now needed to confirm that the variations identified cause ADHD and to identify other variants involved. The exact causes of ADHD are not yet known, but it is currently thought that both genetic and environmental factors play a role.

The results of the current study add to what is known about possible genetic risk factors for ADHD, but do not have immediate implications for the care or treatment for ADHD. As the researchers state, “there is no single gene behind ADHD, and the work is at too early a stage to lead to any test for the disorder.”

Where did the story come from?

The study was carried out by researchers from Cardiff University School of Medicine and other research centres, including deCODE Genetics in Iceland. It was funded by Action Research, the Baily Thomas Charitable Trust, the Wellcome Trust, the UK Medical Research Council and the European Union. The study was published in the peer-reviewed medical journal_ The Lancet._

BBC News, the Daily Mirror, The Guardian and The Daily Telegraph covered this story. In general, they covered the basics of the study accurately, although some coverage incorrectly implied that this was the first evidence of a genetic link with ADHD or that the study ruled out a role for any non-genetic factors in ADHD. The BBC News blog offers a good summary of these issues.

What kind of research was this?

This case-control study looked at whether large deletions and duplications within DNA (called copy number variants or CNVs) might be more common in people with ADHD. If this were the case, it might indicate that the variants play a role in causing the condition. Genetic factors are known to contribute to ADHD, but the exact genes have not been conclusively identified.

Rare CNVs have been found to contribute to conditions such as autism, intellectual disability and schizophrenia, so the researchers wanted to determine whether they might also contribute to ADHD. They were particularly interested in whether ADHD, autism and schizophrenia might all be linked to specific CNVs.

The methods used by the researchers were appropriate for examining the potential role of CNVs in ADHD, and they used various standard quality checks in their DNA analyses.

What did the research involve?

The researchers first compared DNA from 366 UK children with ADHD and 1,156 unrelated, ethnically matched participants drawn from the general population. They looked at whether large, rare CNVs were more common in children with ADHD than in the controls.

The participants were children aged 5 to 17 years, of white UK origin, who were diagnosed with ADHD based on accepted criteria. The researchers did not include any children with autistic spectrum disorders, Tourette’s syndrome, schizophrenia or conditions such as epilepsy. The children’s intellectual ability was assessed using standard intelligence tests.

The researchers looked at single-letter variations in the DNA across the children’s chromosomes to determine where there were CNVs. They also used an additional genetic technique to confirm the presence of the CNVs they identified in children with ADHD. They specifically looked for large CNVs that were rare in the general population (affecting less than 1% of people).

The control subjects were part of a long-running study called the 1958 British Birth Cohort and were born in 1958. They had not been assessed for psychiatric diagnoses, but these were likely to be uncommon.

The researchers first compared the average number of CNVs in cases (children with ADHD) and controls. Because CNVs have been linked to intellectual disability, they also separately looked at the CNVs found in children with ADHD with and without intellectual disability. There were 33 children with ADHD and intellectual disability in the UK sample.

The researchers also specifically looked at 20 areas of the DNA where CNVs associated with autism or schizophrenia have previously been found, to see whether the same areas were affected by CNVs in ADHD.

The researchers then checked some of their results in a separate sample of 825 people with ADHD and 35,243 controls from Iceland.

What were the basic results?

The researchers found that large CNVs were more common in children with ADHD than in controls. They identified 57 large, rare CNVs in children with ADHD and 78 in controls. The average number of CNVs in each individual was about twice as high in cases as in controls, with an average of 0.156 CNVs per child with ADHD and 0.075 CNVs per control. Large CNVs were present in 14% of the children with ADHD and in 7% of controls.

These large, rare CNVs were more common in children with ADHD (both those with and without intellectual disability) than in controls, although they were particularly common in those with intellectual disability. Among children with ADHD and intellectual disability, 36% carried a large CNV compared with 11% of children with ADHD but no intellectual disability. Some regions where CNVs were found in children with ADHD overlapped with some regions where CNVs linked to autism and schizophrenia have been found.

Compared with controls, an area on chromosome 16 had an excess of large CNVs in children with ADHD who did not have intellectual disability. This area also had an excess of CNVs in the people with ADHD from the Icelandic sample compared to Icelandic controls. Two children from the UK sample with ADHD had CNVs in this region. In one case, these were inherited from the child’s mother, and in the other case were the result of a new mutation not inherited from either parent.

How did the researchers interpret the results?

The researchers say their findings provide evidence of an increased number of large copy number variants in people with ADHD. They say that this “refute[s] the hypothesis that ADHD is purely a social construct, which has important clinical and social implications for affected children and their families”.

Conclusion

This study suggests that large, rare deletions and duplications of DNA could play a role in ADHD. Further study is likely to focus on confirming these results in other samples and assessing whether the inheritance of these genetic variations in families is consistent with them being causes of ADHD. Researchers will also want to take a closer look at the functions of the genes affected by these variations, and how changes in these areas might be involved in the condition.

The causes of ADHD are not known, but both genetic and environmental factors are considered to play a role. It is important to note that this study does not rule out a role for other genetic factors in ADHD, nor for environmental factors.