Rare genetic variants confer a high risk of ADHD and implicate neuronal biology

Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a large genetic component<sup>1</sup>. It affects around 5% of children and 2.5% of adults<sup>2</sup>, and is associated with several severe outcomes<sup>3-11</sup>. Common genetic variants associated with the disorder have been identified<sup>12,13</sup>, but the role of rare variants in ADHD is mostly unknown. Here, by analysing rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals, we identify three genes (MAP1A, ANO8 and ANK2; P < 3.07 × 10<sup>-6</sup>; odds ratios 5.55-15.13) that are implicated in ADHD. The protein-protein interaction networks of these three genes were enriched for rare-variant risk genes of other neurodevelopmental disorders, and for genes involved in cytoskeleton organization, synapse function and RNA processing. Top associated rare-variant risk genes showed increased expression across pre- and postnatal brain developmental stages and in several neuronal cell types, including GABAergic (γ-aminobutyric-acid-producing) and dopaminergic neurons. Deleterious variants were associated with lower socioeconomic status and lower levels of education in individuals with ADHD, and a decrease of 2.25 intelligence quotient (IQ) points per rare deleterious variant in a sample of adults with ADHD (n = 962). Individuals with ADHD and intellectual disability showed an increased load of rare variants overall, whereas other psychiatric comorbidities had an increased load only for specific gene sets associated with those comorbidities. This suggests that psychiatric comorbidity in ADHD is driven mainly by rare variants in specific genes, rather than by a general increased load across constrained genes.

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Journal
Nature
Published
2025-11-12
DOI
https://doi.org/10.1038/s41586-025-09702-8
Citations
2
Primary Topic
Attention Deficit Hyperactivity Disorder
Type
article
Field-Weighted Citation Impact
2.94

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article

Rare genetic variants confer a high risk of ADHD and implicate neuronal biology

Jan K. Buitelaar, Trine Tollerup Nielsen, Ditte Demontis, Benjamin M. Neale et al.
2 citations
Nature
Attention Deficit Hyperactivity Disorder
2.94
article

Rare genetic variants confer a high risk of ADHD and implicate neuronal biology

Jan K. Buitelaar, Trine Tollerup Nielsen, Ditte Demontis, Benjamin M. Neale, Preben Bo Mortensen, Nene F. Kobayashi, Anders D. Børglum, Merete Nordentoft, O. Grimm, Barbara Franke, F. Kyle Satterstrom, Marieke Klein, Jakob Grove, Thomas Werge, Esben Agerbo, Jonas Bybjerg‐Grauholm, Andreas Reif, Jinjie Duan, Kasper Lage, Yu-Han H. Hsu, Sarah Kittel‐Schneider, Martine Hoogman, Klaus‐Peter Lesch, Simon Glerup, Greta Pintacuda, Janne Pia Thirstrup, Christian Jacob, Georg Ziegler, Jung‐Fa Tsai, Mark J. Daly, Makayla Martorana, Travis Botts
article en
2 citations

Abstract

Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a large genetic component<sup>1</sup>. It affects around 5% of children and 2.5% of adults<sup>2</sup>, and is associated with several severe outcomes<sup>3-11</sup>. Common genetic variants associated with the disorder have been identified<sup>12,13</sup>, but the role of rare variants in ADHD is mostly unknown. Here, by analysing rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals, we identify three genes (MAP1A, ANO8 and ANK2; P < 3.07 × 10<sup>-6</sup>; odds ratios 5.55-15.13) that are implicated in ADHD. The protein-protein interaction networks of these three genes were enriched for rare-variant risk genes of other neurodevelopmental disorders, and for genes involved in cytoskeleton organization, synapse function and RNA processing. Top associated rare-variant risk genes showed increased expression across pre- and postnatal brain developmental stages and in several neuronal cell types, including GABAergic (γ-aminobutyric-acid-producing) and dopaminergic neurons. Deleterious variants were associated with lower socioeconomic status and lower levels of education in individuals with ADHD, and a decrease of 2.25 intelligence quotient (IQ) points per rare deleterious variant in a sample of adults with ADHD (n = 962). Individuals with ADHD and intellectual disability showed an increased load of rare variants overall, whereas other psychiatric comorbidities had an increased load only for specific gene sets associated with those comorbidities. This suggests that psychiatric comorbidity in ADHD is driven mainly by rare variants in specific genes, rather than by a general increased load across constrained genes.

NatureVol. 649(8098)
Statens Serum Institut (DK), Broad Institute (US), Goethe University Frankfurt (DE), University of Helsinki (FI), Harvard University (US), Radboud University Nijmegen (NL), Aarhus University (DK), University College Cork (IE), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Foundation Center (US), Radboud University Medical Center (NL), Maastricht University (NL), Massachusetts General Hospital (US), Novo Nordisk (United States) (US), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), Finland University (FI), Universitätsklinikum Würzburg (DE), Lundbeck Foundation (DK), University Hospital Frankfurt (DE), Institute for Molecular Medicine Finland (FI), APC Microbiome Institute (IE), Capital Region of Denmark (DK)
Aarhus Universitet, Broad Institute, Simons Foundation Autism Research Initiative, European Commission, Deutsche Forschungsgemeinschaft, ZonMw, Bundesministerium für Bildung und Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Lundbeckfonden, Novo Nordisk, European College of Neuropsychopharmacology, Novo Nordisk Fonden, H. Lundbeck A/S, National Institutes of Health, Horizon 2020 Framework Programme, Stanley Center for Psychiatric Research, Broad Institute, HORIZON EUROPE Framework Programme, National Institute of Mental Health, National Human Genome Research Institute
Openalex Percentile: Top 8%
Attention Deficit Hyperactivity Disorder
2.94
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