Candidate Genetic Pathways for Attention-Deficit/Hyperactivity Disorder (ADHD) Show Association to Hyperactive/Impulsive Symptoms in Children With ADHD
Open accessAbstract
Objective Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD.Method The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales.Results Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ((p)empirical = .007) but not with inattentive symptoms ((p)empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ((p)empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, (p)empirical = .0004; serotonin, (p)empirical = .0149; neuritic outgrowth, (p)empirical = .0452).Conclusion The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to identify biological risk factors involved in this disorder.
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The role of the dopamine, noradrenaline, serotonin and neurite outgrowth systems is supported by GWAS-based gene-set analyses reporting that, as a group, genes regulating these systems were associated with ADHD and hyperactivity or impulsivity.
“Nevertheless, the role of the dopamine, noradrenaline, serotonin and neurite outgrowth systems is supported by genome-wide association studybased gene-set analyses reporting that, as a group, genes regulating these systems were associated with ADHD and hyperactivity or impulsivity 46,49,50 .”
From Attention-deficit/hyperactivity disorder (2015) · cites this paper as [49]
The Discussion (page not specified) reports that the dopamine/noradrenaline, serotonin and neurite-outgrowth pathways were associated with hyperactive/impulsive symptoms in children with ADHD. It also says the case-only design cannot establish whether these pathways contribute to ADHD susceptibility, so the separate implication of an association with ADHD itself is unsupported. (LLM, conf=0.86)
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- Authors
- Bralten, J., Franke, B., Waldman, I., Rommelse, N., Hartman, C., Asherson, P., Banaschewski, T., Ebstein, R. P., Gill, M., Miranda, A., Oades, R. D., Roeyers, H., Rothenberger, A., Sergeant, J. A., Oosterlaan, J., Sonuga-Barke, E., Steinhausen, H.-C., Faraone, S. V., Buitelaar, J. K., & Arias-Vásquez, A.
- Affiliations
- Radboud University Nijmegen (NL)
- Emory University (US)
- University Medical Center Groningen (NL)
- King's College London (GB)
- Heidelberg University (DE)
- National University of Singapore (SG)
- Trinity College Dublin (IE)
- Universitat de València (ES)
- University of Duisburg-Essen (DE)
- Ghent University (BE)
- University of Göttingen (DE)
- Vrije Universiteit Amsterdam (NL)
- University of Basel (CH)
- SUNY Upstate Medical University (US)
- ORCID
- Bralten, Janita
- Franke, Barbara
- Waldman, Irwin
- Rommelse, Nanda
- Hartman, Catharina
- Asherson, Philip
- Banaschewski, Tobias
- Ebstein, Richard P.
- Gill, Michael
- Miranda, Ana
- Roeyers, Herbert
- Rothenberger, Aribert
- Sergeant, Joseph A.
- Oosterlaan, Jaap
- Sonuga-Barke, Edmund
- Steinhausen, Hans-Christoph
- Faraone, Stephen V.
- Buitelaar, Jan K.
- Venue
- Journal of the American Academy of Child & Adolescent Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 52
- Issue
- 11
- Pages
- 1204-1212.e1
- ISSN
- 0890-8567 (ISSN-L)
- OpenAlex
- W2124205806
- Cited by
- 93
- References
- 70
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 10 · 2016: 15 · 2015: 17 · 2014: 12 · 2013: 1
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of the American Academy of Child & Adolescent Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- VU Research Portal (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- DuEPublico (University of Duisburg-Essen) (submittedVersion)
- National University of Singapore (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- GRO (submittedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Eli Lilly and Company
- Pfizer
- Emory University
- Universität Basel
- University of Southampton
- King's College London
- University of Oxford
- National University of Singapore
- Trinity College Dublin
- Universität Heidelberg
- Rijksuniversiteit Groningen
- Radboud Universiteit
- Vrije Universiteit Amsterdam (433-09-242)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (480- 05-003, 433‐09‐242)
- Universitat de València
- Universiteit Gent
- Universitair Medisch Centrum Groningen
- Universität Zürich
- Universität Duisburg-Essen
- Servier
- National Institutes of Health
- State University of New York Upstate Medical University
- Medical Research Council
- National Institute of Mental Health (R01 MH 62873, R01MH081803, R01MH062873)
- Cilag
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- attention deficit hyperactivity disorder, hyperactive-impulsive symptoms, inattention, common genetic variants, serotonergic neurotransmission, neurite outgrowth, gene-environment interaction, symptom severity
- MeSH terms
- Adolescent, Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, Europe, Female, Genotype, Humans, Hyperkinesis, Impulsive Behavior, Israel, Male, Phenotype, Psychiatric Status Rating Scales, Severity of Illness Index, Genetic Association Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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