Rare defects in three key genes markedly increase the risk of ADHD

For decades, researchers have known that ADHD is largely rooted in biology – but the decisive piece has been missing: which specific functions in the brain are affected, and why the risk varies so markedly between individuals.

Now, the largest study to date of rare, damaging genetic variants in ADHD shows that three genes stand out particularly clearly: if a rare, damaging change occurs in one of these genes, the risk of developing ADHD may be 10–15 times higher than normal. For the first time, researchers can therefore link specific genes directly to the biological foundation of the disorder.

The large dataset analysed made it possible to identify locations in the genome where people with ADHD carry more rare, damaging variants than people without ADHD. This finding marks a breakthrough that has increased our understanding of the biology of the disorder and opens new avenues in the search for the underlying mechanisms.

“When we look at the factors that contribute to ADHD, around 70–80% are genetic,” says Ditte Demontis, professor at Aarhus University and lead author. “So it makes very good sense to carry out genetic studies if we want to map the biological mechanisms involved in ADHD. There is still a large proportion of the genes involved in ADHD that we do not know.”

The rare, damaging genetic variants are characterised by destroying the gene so that no functional protein is produced. These variants therefore point precisely to which gene is involved; for that reason, the researchers turned their attention to rare, damaging genetic variants. These are variants that almost no one carries — but when they do occur in a person, they can dramatically alter a gene’s function.

Identifying them required an exceptionally large dataset: nearly 9,000 individuals with ADHD and more than 50,000 without. Only with such a large number of participants was it possible, with statistical certainty, to identify genes that carry an increased burden of rare, damaging variants in people with ADHD compared with those without.

Why chase the very rarest genetic defects?

It was precisely this “missing piece” in the understanding of ADHD genetics that drove the new study. The rare variants examined are errors in the DNA that can destroy a gene or cause it to function incorrectly — and precisely for that reason, this type of genetic variant can have a major effect on, for example, the development of the brain.

“When we see a rare variant that destroys a gene, we know exactly which gene is causally involved,” says Ditte Demontis.

The analysis showed that, although the rare, damaging variants explain only a small part of the probability of developing ADHD, they reveal central mechanisms that may also be affected in people without rare genetic variants, but for other reasons — for example, genetic variants that increase the likelihood of developing ADHD to a lesser degree, but which are more common in the population.

“The identified genes point to biological mechanisms — especially in neurons in the brain — that are affected. The same mechanisms may be affected in people without a rare variant, but where common variants hit the same mechanism,” says Demontis.

Finding rare mutations is like searching for a single printing error in a specific book somewhere in an entire library.

For that reason, the researchers focused on the exome — the small part of DNA that serves as the blueprint for the body’s proteins. The exome makes up around 1–2% of the genome but contains almost the entire recipe, and even small errors here can have noticeable effects.

“It is the protein-coding part of the genome,” explains Ditte Demontis. “Mutations can prevent a protein from being expressed or destroy the function of the protein that is produced, and thus have a strong biological effect.”

From DNA errors to disrupted proteins

To check whether a variant was truly rare, the researchers compared their data with the global gnomAD database. Then the real detective work began: the researchers focused especially on genetic variants that could clearly disrupt a protein’s expression or function.

“We selected the genetic variants that either introduce a stop signal in the gene, so that no functional protein is produced from that gene, or variants that alter the amino acid composition of the protein, causing the protein, for example, to fold incorrectly and therefore not function as it should,” she says.

To gain more information about the function of the three identified genes, the researchers examined how the three proteins encoded by these genes interact with other proteins in nerve cells. This made it possible to map which other proteins in neurons are affected when one of the genes does not function properly — providing a picture of which systems in the brain are disrupted.

“We wanted to understand which other proteins and biological networks may be affected when one of the three genes does not function,” says Demontis.

Finally, the team linked the genetic data with registry data to investigate whether the rare genetic variants also influence real-life outcomes such as education, cognition and income.

Three genes stand out clearly in ADHD

The researchers identified three genes with a statistically significant overrepresentation of damaging genetic variants among people with ADHD compared with those without.

The three identified genes – MAP1A, ANO8 and ANK2 – are all evolutionarily conserved and are involved, among other things, in the development and function of nerve cells.

“These are the first genes for which we can say, with high statistical certainty, that they are enriched with rare, damaging variants among people with ADHD,” says Demontis.

And the effects were remarkably strong.

A single rare variant in MAP1A can increase the risk of ADHD by up to 15 times compared with normal — one of the strongest genetic findings ever reported in the field,” she says. “That does not mean that you develop ADHD simply because you carry such a variant in MAP1A – but the risk becomes markedly higher.”

“We also found overall significantly more damaging variants among people with ADHD than among those without ADHD,” says Ditte Demontis.

The damaging variants were enriched in genes that are evolutionarily conserved — genes that are essential for the development of the brain and nervous system. This is a set of around 3,000 genes that are conserved because, for example, they are critical for brain development.

In addition, the analyses showed that around one in five people with ADHD carried at least one rare, potentially damaging variant in one of the approximately 3,000 evolutionarily conserved genes. Among people without ADHD, the figure was around one in seven. This shows that far from everyone with ADHD carries such a variant — and that a person may carry a rare variant without developing ADHD.

“Damaging, rare genetic variants in evolutionarily conserved genes were identified in around 20% of the individuals with ADHD,” says Demontis. “We saw no difference between men and women with ADHD.”

An entire network of proteins points to ADHD

The researchers also carried out so-called proteome analyses, which showed that the three genes are part of larger networks of proteins that play central roles in how nerve cells develop and communicate. These processes are crucial in the early stages of brain development.

“We found that the protein networks identified for ADHD contain many proteins encoded by genes involved in autism and other developmental disorders — far more than would be expected by chance,” says Demontis. “This indicates that the identified genes affect central processes in the brain — among others synaptic function, which is essential for communication between nerve cells — and that these processes may be disrupted in both ADHD and other developmental disorders.”

When genetics show up in everyday life

Previous studies have shown a negative association between ADHD genetics and genetics involved in cognitive processes and educational attainment. The researchers therefore also examined whether there was a link between rare, damaging genetic variants in evolutionarily conserved genes and educational level as well as measures of economic life circumstances.

People with ADHD who carried a rare, damaging variant had, on average, slightly lower levels of education and income.

“We can see that these variants affect the average level of educational attainment among individuals with ADHD who carry a damaging rare variant, compared with individuals who have ADHD but no damaging variant,” says Demontis.

In a German dataset, the researchers were even able to quantify the cognitive effect: around 2.25 IQ points lower for each rare, damaging variant among individuals with ADHD.

“Finding a signal for similar measures — namely educational attainment and IQ — really supports our results across datasets,” she says.

“When we see the same patterns in independent datasets, it strengthens the evidence that these are not random findings.”

What do the findings mean for our understanding of ADHD?

The new results give researchers a clearer picture of what may lie behind ADHD at the biological level — and why the condition develops differently from person to person. It has long been known that many small genetic changes together increase the likelihood of developing ADHD, but many of the mechanisms remain unknown.

“The rare variants explain only a small part of the overall genetics. They are nevertheless important because they point directly to the genes involved, which can then be linked to biological mechanisms — in this case especially neurons in the brain.”

The results show that the mechanisms driving ADHD overlap with mechanisms known from other developmental disorders such as autism. This raises a central question: how can the same gene be involved in different outcomes in different people?

“We do not know precisely what drives one person biologically in the direction of autism and another toward ADHD,” she says. “It is the combination of both the common and the rare variants that together push development in a particular direction in an individual.”

Next steps: more genes and deeper biology

Identifying three genes is only the beginning. When the next wave of genes is identified, researchers will, for the first time, be able to draw a more complete biological map of ADHD — from the earliest developmental mechanisms to the differences in symptoms seen in individuals.

“We certainly have not found all the genes yet,” says Ditte Demontis. “We need much larger studies to identify more genes involved in ADHD and to obtain a more detailed picture of the biology underlying the development of symptoms.”

The next focus will be to understand what the identified genes actually do. This can be studied, among other approaches, in miniature brains (organoids) and in cultured nerve cells.

“It is obvious that someone should go on to study these genes in organoids or in neurons,” says Demontis. “To understand exactly what is affected when the genes are not expressed or do not function as they should.”