Genetic Variants Drastically Increase the Risk of ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high heritability, the genetic basis of which consists of thousands of variants. However, most of these variants only slightly increase the probability of an ADHD diagnosis.

An international study now shows that so-called "high-effect genetic variants" also play an important role. Researchers from Aarhus University (Denmark) were responsible for the study; other participants included the Broad Institute of MIT and Harvard (USA), Radboud University (Netherlands) and the University Hospital Würzburg (UKW). The scientists have now published the results of their investigations in the scientific journal Nature.

Triggers for a High Susceptibility to ADHD

The key finding of the study: people with rare variants in the three genes MAP1A, ANO8 and ANK2 have a significantly increased risk of ADHD, in some cases by more than fifteen times. Although these genetic variants are very rare, they strongly influence the activity of genes in the nerve cells. In people who carry these variants, the development and communication between the nerve cells can therefore be disrupted, which can lead to ADHD.

"The results show for the first time clearly named genes in which rare, strongly acting variants cause a high susceptibility to ADHD and influence fundamental biological mechanisms," summarises Professor Anders Børglum from the Department of Biomedicine at Aarhus University, the senior author of the study.

Influence on Attention and Impulse Control

The study shows that the rare variants involved in ADHD particularly influence the function of neurones that are of great importance for attention, impulse control and motivation. The effects can already be detected in foetal life and extend into adulthood.

"Our results support the assumption that disorders of brain development and function are central to the development of ADHD," explains Ditte Demontis, Professor at the Department of Biomedicine at Aarhus University and lead author of the study. "Our colleagues at the Broad Institute analysed which proteins interact with the proteins encoded by the three identified ADHD genes and identified a larger network of proteins that also play a role in other neurodevelopmental disorders such as autism and schizophrenia. This provides insights into biological relationships across multiple psychiatric diagnoses."

Effects on Intelligence, Education and Employment

The rare genetic variants not only influence who develops ADHD, but also how those affected fare in the education system and on the labour market. By linking genetic data with Danish register data, the researchers found that people with ADHD and rare variants have, on average, a lower level of education and a lower socio-economic status than those affected without these variants. In adults with ADHD in the Würzburg sample, an average decrease in IQ score of around 2.25 points per rare high-risk variant was observed.

The results expand our understanding of the biological basis of ADHD and could form the basis for future treatment methods. According to the study team, this is just the beginning. Their calculations show that there are many more rare causal variants that can be identified in even larger studies.

Data from almost 1,000 Patients Came from Würzburg

"I am delighted that we in Würzburg were able to make a significant contribution to these important findings," says Professor Klaus-Peter Lesch. The psychiatrist and behavioural scientist worked at the Department of Psychiatry, Psychosomatics and Psychotherapy of University Hospital Würzburg from 1985 to 2023 and is now a senior professor at the Department of Child and Adolescent Psychiatry. From 2010 to 2023, he held the Chair of Molecular Psychiatry and from 2004 to 2011 headed the Clinical Research Unit for Research into Attention Deficit/Hyperactivity Disorder, which was funded by the German Research Foundation (DFG).

The current study included genetic analyses of almost 9,000 people with ADHD and 54,000 people without ADHD. These were combined with analyses of brain cell function and register data on education and socio-economic status. The University Hospital of Würzburg contributed the diagnostic evaluation and biomaterial from almost 1,000 patients with ADHD in adulthood.

ADHD Persists in Adulthood in Many of Those Affected

"ADHD across the lifespan" is one of the joint research focuses of the two clinics for child and adolescent psychiatry and psychiatry, psychosomatics and psychotherapy. The disorder is the most common neurodevelopmental disorder in childhood. In up to 60 per cent of those affected, it persists into adulthood and is associated with considerable psychological distress - for example due to repeated failures or frustration. In addition, many adults with ADHD develop at least one other mental illness in the course of their lives, for example depression, anxiety disorders or addictions.

However, only around half of those affected respond adequately to current forms of treatment, such as psychostimulants or psychotherapeutic procedures. "With our research, we therefore want to gain a better understanding of the neurobiological and psychological causes of ADHD and its frequent concomitant disorders in order to support the urgently needed development of additional therapeutic approaches in the long term," says Dr Georg Ziegler, Senior Consultant and Head of the ADHD in Adults research group.

Publication

Demontis, D., Duan, J., Hsu, YH.H. et al. Rare genetic variants confer a high risk of ADHD and implicate neuronal biology. Nature (2025). https://doi. org/10.1038/s41586-025-09702-8