New research: Variations in ADHD can be traced to genes

ADHD is a complex and highly variable disorder, but the cause of this variability has, until recently, been unknown. Now, however, a Danish-American research team has found a link between genetic variants and some of the differences in ADHD, which may pave the way for individualised treatment and prevention.

There was a time when it was mostly only “boisterous” school-age boys who received a diagnosis of ADHD. Hyperactive and impulsive, they were unable to sit still and caused constant classroom disruption.  “They’re climbing the walls”, was a typical expression used to describe them.

Today, girls, adolescents and adults are also diagnosed with ADHD, because we now know that this developmental disorder is not limited by either sex or age, although most of those diagnosed are boys.

ADHD is a complex neuropsychiatric disorder with variable severity and long-term outcomes. And in some cases, this disorder is accompanied by other diagnoses, including mental disorders such as depression, anxiety, or autism spectrum disorder (ASD). Until now, however, the genetic basis of the differences has been like a “black box”.

Recently, a Danish-American team of researchers lifted the lid of that box, discovering that some of the variability in ADHD patients can be attributed to genes.

Andrew Schork, a researcher in the field of psychiatric genetics at the Institute of Biological Psychiatry, Mental Health Centre Sct. Hans in Roskilde, Denmark, and a Lundbeck Foundation Fellow, established the research team behind the study.  

‘The genetic profiles turned out to be quite different- in significant but promising ways that may ultimately hold potential for prevention and treatment,’ he says.

Researchers identified distinct genetic differences

The study used data on 14,000 Danes with ADHD born between 1981 and 2005. The data come from the iPSYCH cohort, a database of health data, DNA data and social data from 130,000 Danes, of whom around 90,000 have a psychiatric disorder, while the remainder serve as healthy control subjects.

In this study, the researchers compared individuals who “only” have ADHD with individuals who have both ADHD and some additional challenges, for example in the form of another mental disorder. The researchers chose to study a small selection of this type of “secondary outcome” data - focusing on 22 ADHD-associated traits. Among these were cases of ADHD not diagnosed until adulthood and thosewith an additional psychiatric diagnosis, such as anxiety or depression.

The researchers then investigated whether these different traits had a genetic basis. And some of them clearly had.

One of the most striking findings is that people with ADHD, who also have either ASD or also have substance use disorder (SUD), or who were not diagnosed until they reached adulthood, carry genetic variants that appear to correspond to the differences. 

‘These genetic differences can help us gain a better understanding of this developmental disorder,’ Schork explains.

Sonja LaBianca, a postdoc member of Schork’s team, and who led the study, is a medical doctor who has worked with children, adolescents, and adults with ADHD.

‘Our finding confirms that the highly differentiated complications we see in clinical care of patients within the same diagnosis is actually bound up with their genetic profile, and so most likely with their biological makeup, too,’ she says.

Genetic risk score to support mental healthcare

Genetic variants could potentially be used at an early stage to map an individual's risk of disorder, but also perhaps their risk of developing a given complication or certain course. And since the genes control the cells’ production of proteins, they can also reveal novel drug targets. 

Geneticists determine the individual's risk for a disorder as a so-called polygenic risk score (PGS), which indicates the risk carried across the sum total of tens of thousands of small genetic variants in the individual’s genome.

In other words, the disorders are not caused by single, rare, inherited genetic variant but by combinations of thousands of minute variants in the genes that commonly occur and, individually, are of equally minute significance.  Put together, however, in certain combinations with other variants and with lifestyle and environmental factors, such PGS can predict, to some extent, individual risk of having a developmental disorder or of a more negative or positive long-term outcome.

“One day, we might be able to use the polygenetic risk scores for comparison with other risk factors and predict the course of a patient’s disorder, and determine whether, for example, a patient is going to respond to the treatment we have to offer,” explains LaBianca.

And that may prove helpful given that around 10-20 per cent of people with ADHD do not benefit fully from medicinal therapy.

LaBianca does emphasise, however, that she is not expecting to be able to put PRS to use any time soon. The tool is far from being viable for practical use.

‘But demonstrating, as we have here, that there are differences in the genetics, is a huge step in that direction,’ she says.

The backdrop to the study is the dramatic increase in the number of people diagnosed with ADHD. In 2018, around 50,000 children, adolescents and adults in Denmark were on ADHD medication, and by 2022, the number had risen to 86,000.

This increase, which applies not only in Denmark, has led to further research in ADHD internationally, but, explains Schork, in this particular study, the researchers challenge prevailing practices in the field.

‘There’s a tendency among genetics researchers to “lump” people diagnosed with a disorder like ADHD together. But in the real world, patients are not ones or zeros on a spreadsheet, and that view was emphasized by the medical investigators and epidemiologists involved in this study,’ he explains.

‘That led us to examine a greater number of outcomes and different risk scores, and to question the common assumption that the same genes that determine susceptibility to the disorder also determine its long-term outcomes for the individual.’ 

This study is the first of its kind and will be followed up by other, larger-scale studies before the results can be applied in prevention, diagnostics, and treatment. However, Schork hopes that the results may inspire other researchers to pursue an interest in genetic differences.

‘This is demonstrating a concept that there is much to gain, and that we need to account for how individual the patients are, and how different the long-term outcome is for each of them. We have demonstrated that it’s possible to apply genetics in dissecting very complex differences, and this can be transferred to the study of other disorders too.’

The new study accepted for publication in the prestigious scientific journal Nature Genetics was established under the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH).