Rare genetic variants increase the risk of ADHD by up to 15 times
International study shows how rare genetic variants in nerve cells influence brain development
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A new study led by researchers at Aarhus University and involving the University Hospital of Würzburg has identified rare genetic variants that significantly increase the risk of ADHD. The study shows that these variants are expressed particularly in nerve cells in the brain and have a negative impact on cognitive abilities and educational success.
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 likelihood of an ADHD diagnosis.
An international study led by researchers from Aarhus University (Denmark) in collaboration with partners such as the Broad Institute of MIT and Harvard (USA), Radboud University (Netherlands) and the University Medical Center Würzburg (UKW) has now shown that so-called "high-effect genetic variants", i.e. rare genetic variants with a strong effect, also play an important role. The results were published in the journal NATURE.
Disorders of brain development and function are central to the development of ADHD
The researchers found that 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 15 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, strong-acting variants cause a high susceptibility to ADHD and influence fundamental biological mechanisms," summarizes Professor Anders Børglum from the Department of Biomedicine at Aarhus University, the senior author of the study.
The analysis of combined genetic and gene expression data shows that the rare variants involved in ADHD particularly influence the function of dopaminergic and GABAergic neurons. These cell types are of great importance for attention, impulse control and motivation. The effects can already be detected in fetal life and extend into adulthood. "Our results support the assumption that disturbances in 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 analyzed 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 connections 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 labor 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 very pleased that we in Würzburg were able to make a significant contribution to these important findings," says Prof. Dr. Klaus-Peter Lesch. The psychiatrist and behavioral scientist worked at the Department of Psychiatry, Psychosomatics and Psychotherapy from 1985 to 2023 and is now Senior Professor at the Department of Child and Adolescent Psychiatry. From 2010 to 2023, he held the Chair of Molecular Psychiatry and headed the Clinical Research Unit for the Study of Attention Deficit/Hyperactivity Disorder (KFO 125) funded by the German Research Foundation (DFG) from 2004 to 2011.
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.
In up to 60 percent of those affected, ADHD persists into adulthood
"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 percent 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, such as 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 would therefore like 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 research group on ADHD in adulthood.
Note: This article has been translated using a computer system without human intervention. LUMITOS offers these automatic translations to present a wider range of current news. Since this article has been translated with automatic translation, it is possible that it contains errors in vocabulary, syntax or grammar. The original article in German can be found here.
Original publication
Ditte Demontis, Jinjie Duan, Yu-Han H. Hsu, Greta Pintacuda, Jakob Grove, Trine Tollerup Nielsen, Janne Thirstrup, Makayla Martorana, Travis Botts, F. Kyle Satterstrom, ... Merete Nordentoft, Ole Mors, Preben Bo Mortensen, Kasper Lage, Mark J. Daly, Benjamin M. Neale, Anders D. Børglum; "Rare genetic variants confer a high risk of ADHD and implicate neuronal biology"; Nature, 2025-11-12
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