Linking genetics to behavior: from glutamatergic genetic variation via amygdala morphology and fear recognition to youth's callous-unemotional traits and reactive-proactive aggression

Renee Kleine Deters; I Hyun Ruisch; Jilly Naaijen; Pascal-M Aggensteiner; Tobias Banaschewski; Ulrike M E Schulze; Michael C Craig; Arjun Sethi; Josefina Castro-Fornieles; Itziar Flamarique; María José Penzol; Daniel Brandeis; Julia E Werhahn; Jeffrey C Glennon; Jan K Buitelaar; Pieter J Hoekstra; Andrea Dietrich

doi:10.1016/j.bpsc.2025.10.012

Linking genetics to behavior: from glutamatergic genetic variation via amygdala morphology and fear recognition to youth's callous-unemotional traits and reactive-proactive aggression

Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Oct 29:S2451-9022(25)00327-1. doi: 10.1016/j.bpsc.2025.10.012. Online ahead of print.

Authors

Renee Kleine Deters¹, I Hyun Ruisch², Jilly Naaijen³, Pascal-M Aggensteiner⁴, Tobias Banaschewski⁴, Ulrike M E Schulze⁵, Michael C Craig⁶, Arjun Sethi⁶, Josefina Castro-Fornieles⁷, Itziar Flamarique⁷, María José Penzol⁸, Daniel Brandeis⁹, Julia E Werhahn¹⁰, Jeffrey C Glennon¹¹, Jan K Buitelaar¹², Pieter J Hoekstra², Andrea Dietrich²

Affiliations

¹ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Accare Child Study Center, Groningen, The Netherlands; The Research School of Behavioural and Cognitive Neurosciences, University of Groningen, Groningen, The Netherlands. Electronic address: r.kleine.deters@rug.nl.
² Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Accare Child Study Center, Groningen, The Netherlands; The Research School of Behavioural and Cognitive Neurosciences, University of Groningen, Groningen, The Netherlands.
³ Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands.
⁴ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Germany.
⁵ Department of Child and Adolescent Psychiatry/Psychotherapy, University Hospital, University of Ulm, Ulm, Germany.
⁶ Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁷ Child and Adolescent Psychiatry and Psychology Department 2021SGR01319, Hospital Clinic of Barcelona, CIBERSAM, IDIBAPS, Department of Medicine, Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
⁸ Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, ISCIII, School of Medicine, Universidad Complutense, Madrid, Spain.
⁹ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
¹⁰ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital, University of Zurich, Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
¹¹ Conway Institute of Biomolecular and Biomedical Sciences, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
¹² Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands; Karakter Child and Adolescent Psychiatry University Center, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands.

PMID: 41173193
DOI: 10.1016/j.bpsc.2025.10.012

Abstract

Background: Although glutamatergic genetic variation, reduced amygdala volume, and impaired fear recognition have been linked to CU traits and aggression, the pathways connecting these constructs remain unclear. Therefore, we examined associations between genetic proxies of glutamine/glutamate blood levels, and CU traits, reactive and proactive aggression, and the mediating role of amygdala morphology and fear recognition.

Methods: Our pooled case-control sample consisted of 278 youths (8‒18 years, n_male=203) with (n=177) and without (n=101) clinically significant aggressive behavior and/or disruptive behavior disorders (DBDs), who participated in a European multi-center study. We used continuous scores for CU traits and aggression, polygenic scores (PGS) for blood levels of glutamine/glutamate, and T1-weighted magnetic resonance images for calculating amygdala volume and vertex-wise shape analyses. We applied path analysis to test direct and total associations and mediation effects.

Results: Glutamine PGS were negatively associated with CU traits. Glutamate PGS were positively associated with amygdala volume and fear recognition, which were in turn negatively associated with CU traits and proactive aggression; fear recognition also with reactive aggression. The total path between glutamate PGS and CU traits was also significant, and mediated by fear recognition.

Conclusions: Our results suggest that 1) glutaminergic genetic variation is associated with CU traits, 2) glutamatergic genetic variation is associated with amygdala volume and fear recognition, and 3) indirectly with CU traits through fear recognition. Overall, we provide support for an etiological pathway underlying CU traits encompassing glutaminergic/glutamatergic genetic variation, amygdala volume, and fear recognition and the relevance of using PGS for glutamate/glutamine blood metabolites.

Keywords: Callous-unemotional traits; amygdala; fear recognition; proactive aggression; reactive aggression.