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Cited by 142Attention Deficit Hyperactivity DisorderAutism Spectrum Disorder ResearchGenetic Associations and Epidemiology

Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism

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Naaijen, J, Bralten, J, Poelmans, G, The IMAGE consortium, Faraone, Stephen, Asherson, Philip, Banaschewski, Tobias, Buitelaar, Jan +15 more·2017·Translational Psychiatry
DOI 10.1038/tp.2016.273PMC PMC5545734
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Abstract

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.

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  • Higher glutamate levels and reduced GABA levels have been observed in children with ADHD, which indicates a bias towards neuron excitation that might be implicated in hyperactivity induction, although without a firm conclusion.

    “In this sense, higher glutamate levels and reduced GABA levels have been observed in children with ADHD, which indicates a bias towards neuron excitation that might be implicated in hyperactivity induction, although without a firm conclusion [101].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [101]

    The Introduction reports decreased prefrontal GABA in children with ADHD and increased glutamatergic levels in a separate study. The Results and Discussion link glutamate-related genetic variation to hyperactivity/impulsivity, but the Discussion says the study cannot determine the direction of effects; it does not establish an excitatory bias or show that such a bias induces hyperactivity. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Higher glutamate levels have been observed in children with ADHD.

    “In this sense, higher glutamate levels have been observed in children with ADHD [101].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [101]

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Authors
Naaijen, J., Bralten, J., Poelmans, G., The IMAGE consortium, Faraone, S., Asherson, P., Banaschewski, T., Buitelaar, J., Franke, B., P Ebstein, R., Gill, M., Miranda, A., D Oades, R., Roeyers, H., Rothenberger, A., Sergeant, J., Sonuga-Barke, E., Anney, R., Mulas, F., Steinhausen, H.-C., Glennon, J. C., Franke, B., & Buitelaar, J. K.
Affiliations
  • Radboud University Medical Center (NL)
  • King's College London (GB)
  • Radboud University Nijmegen (NL)
  • Universitat de València (ES)
  • University of Duisburg-Essen (DE)
  • University of Göttingen (DE)
  • Vrije Universiteit Amsterdam (NL)
  • State University of New York (US)
  • St. James's Hospital (IE)
Corresponding author
Naaijen, J
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2017-01-10
Volume
7
Issue
1
Pages
e999-e999
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2016.273
PMC
PMC5545734
OpenAlex
W2570496985
Cited by
142
References
15
Citations by year
2026: 14 · 2025: 13 · 2024: 13 · 2023: 19 · 2022: 22 · 2021: 12 · 2020: 14 · 2019: 16 · 2018: 11 · 2017: 8
FWCI
11.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (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, cc-by)
  • National University of Singapore (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Universität Basel
  • European Federation of Pharmaceutical Industries and Associations (FP7/20072013)
  • University of Southampton
  • King's College London (278948, 115300)
  • European Commission (2007–2013, FP7 2007-2013, 278948, 115300, FP7/2007)
  • National University of Singapore
  • Trinity College Dublin
  • Universität Heidelberg
  • Radboud Universiteit
  • Vrije Universiteit Amsterdam (FP7/2007-2013, 278948)
  • Universitat de València
  • Universiteit Gent
  • Universität Zürich
  • Universität Duisburg-Essen
  • Innovative Medicines Initiative (FP7/2007‐2013, 115300)
  • National Institutes of Health (FP7/2007-2013)
  • Medical Research Council (FP7/20072013, 115300, MR/L010305/1)
  • National Institute of Mental Health (R01MH081803, R01MH062873)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
attention deficit hyperactivity disorder, autism spectrum disorder, glutamate, GABA, gene set analysis, hyperactivity/impulsivity, inattention, response inhibition, excitatory and inhibitory neurotransmitters, genetic risk variants, comorbidities
MeSH terms
Autism Spectrum Disorder, Adolescent, Attention Deficit Disorder with Hyperactivity, Autistic Disorder, Calcium-Binding Proteins, Child, Child, Preschool, Female, gamma-Aminobutyric Acid, Humans, Male, Nerve Tissue Proteins, Receptors, GABA-A, Severity of Illness Index, Receptors, N-Methyl-D-Aspartate, Receptors, AMPA, Receptors, Metabotropic Glutamate, Glutamic Acid, Amino Acid Transport System y+L, Fusion Regulatory Protein 1, Light Chains

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