Miguel Mealha Estrada

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition that begins in childhood and often continues into adulthood. It affects around 5% of children and about 2.5% of adults worldwide. ADHD is associated with difficulties in attention, impulsivity and hyperactivity, and it is also linked to a range of serious life outcomes, including increased risks of substance misuse, accidents, unemployment, lower educational attainment and mental health problems.

For many years, research has shown that ADHD has a strong genetic component. Studies of twins estimate that around 77–88% of the risk of developing ADHD can be explained by genetic factors. Large genetic studies have identified many common genetic variants that each make a small contribution to risk. However, these common variants do not fully explain why ADHD runs in families. Researchers have therefore turned their attention to rare genetic variants — changes in DNA that occur infrequently in the population but may have a larger biological impact.

In this study, published in Nature Rare genetic variants researchers investigated the role of rare genetic changes that affect protein-coding regions of genes (known as exomes). These regions contain instructions for building proteins, which carry out most functions in cells. By analysing exome sequencing data from 8,895 people diagnosed with ADHD and 53,780 people without ADHD, the team aimed to discover whether rare, potentially harmful variants increase the risk of ADHD and to understand the biological pathways involved.

Identifying three high-risk genes

The researchers discovered three genes, MAP1A, ANO8 and ANK2, in which rare damaging variants were significantly more common in people with ADHD than in those without the condition. These variants were uncommon in the general population but, when present, were associated with a much higher increase in ADHD risk than the common variants previously identified.

Importantly, the risk linked to these rare variants was several times greater than that associated with common genetic variants. This suggests that although rare variants occur in fewer individuals, their biological effects can be substantial.

Two of the genes (MAP1A and ANO8) were mainly affected by rare “protein-truncating” variants, changes that disrupt the structure of the resulting protein, often preventing it from functioning properly. The third gene (ANK2) showed increased risk from both truncating variants and other strongly damaging changes.

Although these findings are significant, it is important to note that these rare variants are not responsible for most cases of ADHD. Only around one in five individuals with ADHD carried highly damaging variants in genes that are particularly sensitive to disruption. This confirms that ADHD is genetically complex and influenced by many different factors.

What do these genes do?

The three identified genes are involved in important processes in brain cells:

• MAP1A plays a role in organising microtubules, structural components that help maintain the shape of neurons and support the transport of materials within them.
• ANK2 is involved in maintaining the stability of cell membranes and plays a role in calcium signalling, which is essential for communication between neurons.
• ANO8 is linked to ion transport across cell membranes, which is crucial for electrical signalling in the brain.

Together, these findings suggest that rare variants affecting the structure of neurons, their internal transport systems and their electrical signalling may contribute to ADHD.

Broader biological pathways

The researchers did not stop at identifying individual genes. They also examined how the proteins produced by these genes interact with other proteins in brain cells. By studying protein–protein interaction networks, they found that these genes are connected to broader networks involved in:

• Synapse function (the connections between neurons)
• Cytoskeleton organisation (the structural framework of cells)
• RNA processing (how genetic instructions are managed within cells)

These networks were enriched for genes previously linked to other neurodevelopmental disorders, such as autism and developmental disorders. This suggests that ADHD shares some biological pathways with other conditions affecting brain development.

Effects across brain development

To understand when these genes might be important, the researchers examined their expression in the brain across different stages of development, from before birth to adulthood. They found that the top ADHD risk genes were expressed at higher-than-average levels throughout most stages of brain development.

Interestingly, some genes showed differences in timing. For example, MAP1A was more strongly expressed after birth, while ANO8 showed higher expression before birth. This suggests that rare variants may influence brain development at multiple stages, not only during early childhood.

Specific brain cell types involved

The study also explored which types of brain cells are most affected by rare ADHD risk genes. Using single-cell RNA sequencing data, the researchers found that these genes were particularly active in:

• Dopaminergic neurons (which use dopamine as a neurotransmitter)
• GABAergic neurons (which use GABA as a neurotransmitter)
• Developing neuronal precursor cells

Dopamine has long been linked to ADHD, partly because stimulant medications such as methylphenidate increase dopamine availability in the brain and can reduce ADHD symptoms. The finding that rare genetic risk also converges on dopamine-related neurons strengthens this biological link.

The involvement of GABAergic neurons suggests that inhibitory signalling in the brain may also play an important role in ADHD.

Cognitive and socioeconomic outcomes

Beyond diagnosis, the study examined how rare damaging variants affect life outcomes among individuals with ADHD. By linking genetic data to Danish national registers, the researchers analysed educational attainment and socioeconomic status.

They found that individuals with ADHD who carried rare damaging variants in highly constrained genes were:

• More likely to have completed only primary school
• More likely to experience lower socioeconomic status, such as unemployment or reliance on social benefits

These associations remained significant even after excluding individuals with intellectual disability.

In a separate clinical sample of adults with ADHD, each ultra-rare damaging variant was associated with a reduction of approximately 2.25 IQ points. While this effect is modest at the individual level, it demonstrates that rare variants can influence cognitive functioning.

These findings show that rare genetic variants not only increase the likelihood of ADHD but may also contribute to differences in cognitive performance and life opportunities.

Interaction between rare and common variants

ADHD is influenced by both rare variants (with larger effects) and common variants (with smaller individual effects but widespread influence). The researchers examined how these two types of genetic risk interact.

They found that rare and common variants appear to act additively. In other words, individuals who carry both rare damaging variants and a high load of common risk variants have the greatest overall risk. The presence of a rare damaging variant increased ADHD risk by an amount comparable to a substantial increase in common genetic risk.

This additive pattern suggests that ADHD arises from a combination of genetic influences across the full spectrum of variant frequencies.

ADHD and co-occurring conditions

Many individuals with ADHD also have other conditions, such as autism, schizophrenia, substance use disorders or intellectual disability. The study investigated whether rare variants were generally more common in people with ADHD who had additional diagnoses.

The strongest increase in rare variant burden was seen in individuals with ADHD and intellectual disability. However, for other psychiatric comorbidities, there was not a general increase across all genes. Instead, increased rare variant burden tended to be confined to gene sets specifically associated with those conditions.

This suggests that co-occurring psychiatric conditions may arise from overlapping but partly distinct genetic influences, rather than from a simple increase in overall genetic burden.

The researchers also compared rare variant patterns between ADHD and autism and found substantial overlap. This reinforces the idea that these neurodevelopmental conditions share biological mechanisms.

Overall conclusions

This large-scale exome sequencing study provides important new insights into the genetic architecture of ADHD Rare genetic variants confer a …. It shows that:

• Rare damaging variants in specific genes significantly increase ADHD risk.
• These genes are involved in neuronal structure, synaptic function and ion signalling.
• Rare variants affect key brain cell types, particularly dopaminergic and GABAergic neurons.
• Rare genetic risk contributes to cognitive outcomes and socioeconomic differences.
• Rare and common genetic variants combine additively to influence risk.
• ADHD shares rare genetic risk pathways with other neurodevelopmental disorders.

Although the three identified genes explain only a small fraction of total genetic risk, they provide valuable clues about the biological processes underlying ADHD. As research continues and larger samples are analysed, more rare risk genes are likely to be discovered.

Ultimately, understanding how genetic variants affect brain development and function may support the development of more targeted interventions and improved support strategies for individuals with ADHD.

Link to the article: https://www.nature.com/articles/s41586-025-09702-8

by Miguel Mealha Estrada