Summary: A large international genetic study has identified rare, high-impact variants in three genes—MAP1A, ANO8 and ANK2—that substantially increase the risk of attention-deficit/hyperactivity disorder (ADHD). Although these variants are uncommon, they have strong biological effects on genes expressed in dopaminergic and GABAergic neurons and appear to influence brain development from fetal stages into adulthood.
Carriers of these rare variants diagnosed with ADHD also show lower average IQ scores and poorer educational and socioeconomic outcomes. The results represent an important advance toward pinpointing specific biological pathways involved in ADHD and identifying potential targets for future treatments.
Key Facts:
- Rare, high-impact variants: Rare damaging variants in MAP1A, ANO8 and ANK2 can increase the risk of ADHD by up to 15-fold in carriers.
- Targeted neuronal effects: These variants disproportionately affect genes active in dopaminergic and GABAergic neurons, cell types that regulate attention, impulse control and motivation.
- Life and cognitive impact: Among individuals with ADHD, carriers of these variants tend to have lower educational attainment, reduced socioeconomic status and modest reductions in measured IQ.
Source: Aarhus University
Background: ADHD is a neurodevelopmental condition with a strong genetic basis. While many common genetic variants each contribute a small increase in ADHD risk, this study demonstrates that rare coding variants with large effects also play a meaningful role.
Led by researchers at iPSYCH, Aarhus University, the international analysis combined exome-sequencing data, brain-cell expression profiles and national registry information. The peer-reviewed findings, published in Nature, highlight three genes—MAP1A, ANO8 and ANK2—where rare damaging variants confer substantially elevated ADHD risk in carriers.
Although these variants are scarce in the population, when present they appear to disrupt the function of genes expressed in neurons. Such disruptions can impair neural development and communication and thereby contribute to the emergence of ADHD symptoms.
“For the first time we can point to specific genes in which rare variants give a high predisposition to ADHD,” says Professor Anders Børglum, Department of Biomedicine at Aarhus University and senior author of the study. “These variants are likely highly damaging to the genes involved and reveal precise biological mechanisms to investigate further.”
Impact on brain development and neuronal biology
By integrating genetic findings with gene expression data across cell types and developmental stages, the researchers showed that implicated rare variants are especially active in dopaminergic and GABAergic neurons. These neuronal types are central to processes such as attention regulation, impulse control and motivation, and their dysfunction can contribute to ADHD pathology.
The expression patterns associated with the top rare-variant genes are evident during prenatal brain development and persist through later stages, indicating that the genetic impact begins early in fetal life and continues into adulthood.
First author Ditte Demontis, Professor at the Department of Biomedicine, explains that the study also mapped protein interactions of the three implicated genes, revealing a broader network that overlaps with genes related to other neurodevelopmental disorders, including autism and schizophrenia. These connections offer insight into shared biological pathways across psychiatric diagnoses.
Consequences for cognition, education and work
The study examined how rare variants affect real-world outcomes by linking genetic data to Danish registry records. Individuals with ADHD who carry rare damaging variants had, on average, lower levels of education and socioeconomic status compared with people with ADHD who do not carry these variants.
In a subset of adults with ADHD, each additional rare deleterious variant was associated with an average decrease of about 2.25 IQ points, suggesting modest but measurable cognitive effects that may influence educational performance and employment prospects.
Co-first author Jinjie Duan, a postdoctoral researcher in the Aarhus group, notes that these findings indicate greater cognitive and functional challenges for some individuals with ADHD and highlight the importance of considering rare genetic variation when assessing prognosis and support needs.
Scientific and clinical implications
This research expands our understanding of ADHD’s biological roots by identifying specific high-effect causal genes. Knowing causal genes and their networks allows researchers to design focused mechanistic studies that can explore how disruptions to these genes alter neuronal development and function. Such work could point to novel therapeutic strategies and interventions targeting the underlying biology of ADHD.
The authors emphasize that these results represent an early but important step. Their analyses suggest many additional rare causal variants remain to be discovered as sample sizes grow. In fact, the study also highlights 17 additional genes with rare variants that are likely causal and merit further investigation.
Study design and collaborators
- The core genetic analysis included exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals from the Danish iPSYCH cohort, supplemented by brain cell expression data and national registry information on education and socioeconomic status.
- The principal finding is that rare damaging variants in MAP1A, ANO8 and ANK2 are associated with up to a 15-fold increased risk of ADHD. These variants predominantly affect genes expressed in the brain, especially in dopaminergic and GABAergic neurons, and are associated with lower educational attainment, socioeconomic outcomes and IQ among carriers.
- The research was led by Aarhus University in collaboration with the Broad Institute of MIT and Harvard, Radboud University, University Hospital Würzburg and other international partners, with funding from the Lundbeck Foundation, the Novo Nordisk Foundation and multiple international funders. The full paper is published in Nature.
Key Questions Answered
Q: What did researchers discover about genetic risk for ADHD?
A: They identified rare, high-impact variants in MAP1A, ANO8 and ANK2 that can raise ADHD risk by up to 15-fold in carriers.
Q: How do these variants affect the brain?
A: The variants disrupt genes that are active in dopaminergic and GABAergic neurons from fetal development through adulthood, affecting attention, motivation and impulse control.
Q: Do these variants influence life outcomes?
A: Yes. People with ADHD who carry these rare variants show lower average IQ, reduced educational attainment and lower socioeconomic status compared with non-carriers.
Editorial Notes
- This article was prepared by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was provided by staff to clarify scientific findings.
About this ADHD and genetics research news
Author: Jakob Christensen
Source: Aarhus University
Contact: Jakob Christensen, Aarhus University
Image: The image is credited to Neuroscience News
Original Research: Open access. “Rare genetic variants confer a high risk of ADHD and implicate neuronal biology” by Anders Børglum et al., published in Nature.
Abstract
Rare genetic variants confer a high risk of ADHD and implicate neuronal biology
Attention-deficit/hyperactivity disorder (ADHD) is an early-onset neurodevelopmental disorder with a substantial genetic component. It affects roughly 5% of children and 2.5% of adults and is associated with significant long-term consequences. While many common genetic variants linked to ADHD have been identified, the contribution of rare coding variants has been less clear.
This study analyzed rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 controls. It implicates three genes—MAP1A, ANO8 and ANK2 (P < 3.07 × 10−6; odds ratios 5.55–15.13)—as carrying rare variants that significantly increase ADHD risk. The protein interaction networks around these genes are enriched for rare-variant risk genes involved in cytoskeleton organization, synapse function and RNA processing, and overlap with genes associated with other neurodevelopmental conditions.
Top associated rare-variant genes show increased expression across prenatal and postnatal brain development and in several neuronal cell types, including GABAergic and dopaminergic neurons. Deleterious rare variants were linked to lower socioeconomic status and educational attainment among people with ADHD, and an average reduction of about 2.25 IQ points per rare deleterious variant in a sample of adults with ADHD (n = 962). The analyses also indicate that psychiatric comorbidity in ADHD tends to arise from rare variants in specific genes rather than an overall increased burden across constrained genes.