The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis
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BACKGROUND: Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC). METHODS: Our sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach. RESULTS: In the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described. DISCUSSION: A genetic influence on monoaminergic involvement in impulsivity shown by children with ADHD was found. There were trends for separate and overlapping influences on impulsive-aggressive behavior and cognitive impulsivity, where an association with PNMT (and arousal mechanisms affected by its activity) was more clearly involved in the latter. Serotonergic and dopaminergic mechanisms were implicated in both forms of impulsivity with a wider range of serotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity. These preliminary results should be followed up with an examination of environmental influences and associations with performance on tests of impulsivity in the laboratory.
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The 3 R allele (p = 0.014) and rs3758653 C/C genotype were nominally associated with aggressive behavioral impulsivity in the International Multicenter ADHD Genetics (IMAGE) study.
“while the 3 R allele (p = 0.014) and rs3758653 C/C genotype were nominally associated with aggressive behavioral impulsivity in the International Multicenter ADHD Genetics (IMAGE) study [80].”
From Genetics of child aggression, a systematic review (2024) · cites this paper as [80]
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Dorsal raphe neuronal activities are modulated by methylphenidate
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Morton, R. A., Yanagawa, Y., & Valenzuela, C. F. (2015) · eNeuro · doi:10.1523/eneuro.0079-15.2015 · Cited by 17 · see citing works
Richendrfer, H. A., & Créton, R. (2017) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2017.10.009 · Cited by 17 · see citing works
Dinu, L. M., Phattharakulnij, N., & Dommett, E. J. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-022-02478-5 · Cited by 20 · see citing works
Jackson, E. F., Riley, T. B., & Overton, P. G. (2025) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-025-09610-y · Cited by 18 · see citing works
- Authors
- Oades, R. D., Lasky-Su, J., Christiansen, H., Faraone, S. V., Sonuga-Barke, E. J. S., Banaschewski, T., Chen, W., Anney, R. J. L., Buitelaar, J. K., Ebstein, R. P., Franke, B., Gill, M., Miranda, A., Roeyers, H., Rothenberger, A., Sergeant, J. A., Steinhausen, H.-C., Taylor, E. A., Thompson, M., & Asherson, P.
- Affiliations
- University of Duisburg-Essen (DE)
- Brigham and Women's Hospital (US)
- SUNY Upstate Medical University (US)
- Ghent University (BE)
- Central Institute of Mental Health (DE)
- University of Southampton (GB)
- St. James's Hospital (IE)
- Radboud University Nijmegen (NL)
- Herzog Hospital (IL)
- Universitat de València (ES)
- University of Göttingen (DE)
- Vrije Universiteit Amsterdam (NL)
- University of Zurich (CH)
- Corresponding author
- Oades, Robert D.
- ORCID
- Lasky-Su, Jessica
- Christiansen, Hanna
- Faraone, Stephen V.
- Sonuga-Barke, Edmund J.S.
- Banaschewski, Tobias
- Chen, Wai
- Anney, Richard J.L.
- Buitelaar, Jan K.
- Ebstein, Richard P.
- Franke, Barbara
- Gill, Michael
- Miranda, Ana
- Roeyers, Herbert
- Rothenberger, Aribert
- Sergeant, Joseph A.
- Steinhausen, Hans-Christoph
- Taylor, Eric A.
- Thompson, Margaret
- Asherson, Philip
- Venue
- Behavioral and Brain Functions
- Published
- 2008
- Volume
- 4
- Issue
- 1
- Pages
- 48
- ISSN
- 1744-9081 (ISSN-L)
- PMC
- PMC2577091
- OpenAlex
- W2126107189
- Cited by
- 200
- References
- 97
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 20 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 5 · 2019: 12 · 2018: 6 · 2017: 12 · 2016: 13 · 2015: 16 · 2014: 11 · 2013: 9 · 2012: 21
- FWCI
- 10.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Behavioral and Brain Functions (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- National University of Singapore (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DuEPublico (University of Duisburg-Essen) (submittedVersion, cc-by)
- ePrints Soton (University of Southampton) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- GRO (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- University of Southampton
- Radboud Universiteit
- National Institutes of Health
- Medical Research Council
- Economic and Social Research Council
- National Institute of Mental Health (R01MH062873)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- impulsivity, cognitive impulsivity, serotonin, phenylethanolamine N-methyltransferase, brain-derived neurotrophic factor, dopamine receptor genes, HTR2A, HTR3B, tryptophan hydroxylase 2, monoaminergic systems, single nucleotide polymorphisms, genetic association
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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.
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