Estimating differing causal roles of glutamate and GABA genes on brain and behavior in autism

Abstract The excitatory/inhibitory (E/I) imbalance theory suggests that excitatory and inhibitory alterations underlies autism characteristics. However, genetic underpinnings of this imbalance and its impact on brain function and behavior remains unclear. We explored causal links between glutamate and GABA gene-set polygenic scores (PGS) for autism and core autism characteristics, putting particular attention on the restricted- and repetitive behaviors (RRBs) domain by including functional activity (fMRI) during inhibitory control (in the anterior cingulate cortex (ACC) and striatum). Causal links between genes, brain and behavior was evaluated using Bayesian Constraint-based Causal Discovery (BCCD) algorithms, to build causal models of these relationships in a discovery sample (LEAP cohort: autistic = 343, neurotypical = 253) and two generalization cohorts with partially overlapping measures (TACTICS cohort: autistic = 60, neurotypical = 100, Simon Simplex Collection: autistic = 2756). In the discovery sample, we found a causal link between glutamate PGS and core clinical characteristics of autism, particularly the communication domain (Autism Diagnostic Interview-Revised) in autistic participants, with 95% reliability. We did not find links between functional activity during inhibitory control and other measures. For one generalization cohort, we further report on the impact of 1 H-MRS measures of glutamate, identifying a causal link between GABA autism PGS on ACC glutamate concentrations. Not all links were identified in the generalization cohorts, which may be due to clinical and genetic differences between the cohorts. While our results reinforce the previously found association between glutamate genes and core clinical autism behaviors, task-based functional activity may not be causally related to RRBs.

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Publication Details

Journal
Translational Psychiatry
Published
2026-08-24
DOI
https://doi.org/10.1038/s41398-026-04361-3
Primary Topic
Autism Spectrum Disorder Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Estimating differing causal roles of glutamate and GABA genes on brain and behavior in autism

Tom Claassen, I. Hyun Ruisch, Anna Kaiser, Jan K. Buitelaar et al.
Translational Psychiatry
Autism Spectrum Disorder Research
article

Estimating differing causal roles of glutamate and GABA genes on brain and behavior in autism

Tom Claassen, I. Hyun Ruisch, Anna Kaiser, Jan K. Buitelaar, Christine Ecker, Tobias Banaschewski, Luke Mason, Daniel Brandeis, Tony Charman, Declan Murphy, Steven Williams, Julian Tillmann, Jilly Naaijen, Pascal-M. Aggensteiner, Sven Bölte, Christian F. Beckmann, Viola Hollestein, Emily J. H. Jones, David J. Lythgoe, Nicolaas A.J. Puts, Bob Oranje, Sarah Baumeister, Rosemary Holt, Thomas Bourgeron, Eva Loth, Geert Poelmans, Ward De Witte
article en

Abstract

Abstract The excitatory/inhibitory (E/I) imbalance theory suggests that excitatory and inhibitory alterations underlies autism characteristics. However, genetic underpinnings of this imbalance and its impact on brain function and behavior remains unclear. We explored causal links between glutamate and GABA gene-set polygenic scores (PGS) for autism and core autism characteristics, putting particular attention on the restricted- and repetitive behaviors (RRBs) domain by including functional activity (fMRI) during inhibitory control (in the anterior cingulate cortex (ACC) and striatum). Causal links between genes, brain and behavior was evaluated using Bayesian Constraint-based Causal Discovery (BCCD) algorithms, to build causal models of these relationships in a discovery sample (LEAP cohort: autistic = 343, neurotypical = 253) and two generalization cohorts with partially overlapping measures (TACTICS cohort: autistic = 60, neurotypical = 100, Simon Simplex Collection: autistic = 2756). In the discovery sample, we found a causal link between glutamate PGS and core clinical characteristics of autism, particularly the communication domain (Autism Diagnostic Interview-Revised) in autistic participants, with 95% reliability. We did not find links between functional activity during inhibitory control and other measures. For one generalization cohort, we further report on the impact of 1 H-MRS measures of glutamate, identifying a causal link between GABA autism PGS on ACC glutamate concentrations. Not all links were identified in the generalization cohorts, which may be due to clinical and genetic differences between the cohorts. While our results reinforce the previously found association between glutamate genes and core clinical autism behaviors, task-based functional activity may not be causally related to RRBs.

Translational Psychiatry
Goethe University Frankfurt (DE), Roche (Switzerland) (CH), Radboud University Nijmegen (NL), Institut Pasteur (FR), University of Freiburg (DE), King's College - North Carolina (US), Wellcome Centre for Human Neuroimaging (GB), King's College London (GB), University of Zurich (CH), Curtin University (AU), Heidelberg University (DE), University of Cambridge (GB), University Medical Center Freiburg (DE), Glostrup Hospital (DK), University Hospital Heidelberg (DE), University Medical Center (US), Radboud University Medical Center (NL), Karolinska Institutet (SE), ETH Zurich (CH), Don Law Institute (RU), Institute of Cognitive and Brain Sciences (US), Central Institute of Mental Health (DE), Radboud Institute for Molecular Life Sciences (NL), Dutch Expert Centre for Screening (NL), Don State Agrarian University (RU), Swiss Integrative Center for Human Health (CH), AKAD University (DE), University Hospital Frankfurt (DE), Stockholm Health Care Services (SE), Karakter (NL), Institute of Mental Health (RS), Friedrich Schiller University Jena (DE), Medical Research Council (GB), Birkbeck, University of London (GB)
Autism Speaks, European Federation of Pharmaceutical Industries and Associations, Simons Foundation Autism Research Initiative, European Commission
Openalex Percentile: Top 100%
Autism Spectrum Disorder Research
DOIOpen Access PDFOpenAlex
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