Associations between epilepsy-related polygenic risk and brain morphology in childhood

Extensive neuroimaging research in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) has identified brain atrophy as a disease phenotype. While it is also related to a complex genetic architecture, the transition from genetic risk factors to brain vulnerabilities remains unclear. Using a population-based approach, we examined the associations between epilepsy-related polygenic risk for HS (PRS-HS) and brain structure in healthy developing children, assessed their relation to brain network architecture, and evaluated its correspondence with case-control findings in TLE-HS diagnosed patients relative to healthy individuals. We used genome-wide genotyping and structural T1-weighted MRI of 3826 neurotypical children from the Adolescent Brain Cognitive Development (ABCD) study. Surface-based linear models related PRS-HS to cortical thickness measures, and subsequently contextualized findings with structural and functional network architecture based on epicentre mapping approaches. Imaging-genetic associations were then correlated to atrophy and disease epicentres in 785 patients with TLE-HS relative to 1512 healthy controls aggregated across multiple sites. Higher PRS-HS was associated with decreases in cortical thickness across temporo-parietal as well as fronto-central regions of neurotypical children. These imaging-genetic effects were anchored to the connectivity profiles of distinct functional and structural epicentres. Compared with disease-related alterations from a separate epilepsy cohort, regional and network correlates of PRS-HS strongly mirrored cortical atrophy and disease epicentres observed in patients with TLE-HS and were highly replicable across different studies. Findings were consistent when using statistical models controlling for spatial autocorrelations and robust to variations in analytic methods. Capitalizing on recent imaging-genetic initiatives, our study provides novel insights into the genetic underpinnings of structural alterations in TLE-HS, revealing common morphological and network pathways between genetic vulnerability and disease mechanisms. These signatures offer a foundation for early risk stratification and personalized interventions targeting genetic profiles in epilepsy.

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Journal
Brain
Published
2025-08-08
DOI
https://doi.org/10.1093/brain/awaf259
Citations
2
Primary Topic
Functional Brain Connectivity Studies
Type
article
Field-Weighted Citation Impact
2.86

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article

Associations between epilepsy-related polygenic risk and brain morphology in childhood

Orrin Devinsky, Colin P. Doherty, John S. Duncan, Boris C. Bernhardt et al.
2 citations
Brain
Functional Brain Connectivity Studies
2.86
article

Associations between epilepsy-related polygenic risk and brain morphology in childhood

Orrin Devinsky, Colin P. Doherty, John S. Duncan, Boris C. Bernhardt, Raviteja Kotikalapudi, Christian Rummel, Lorenzo Caciagli, Aoife Griffin, Zhiqiang Zhang, Matteo Lenge, Renzo Guerrini, Clara F. Weber, Erik Kaestner, Terence John O'Brien, Domenico Tortora, Maria Eugenia Caligiuri, Esmaeil Davoodi‐Bojd, B.T. Thomas Yeo, Reetta Kälviäinen, Casey Paquola, Stefano Meletti, Pascal Martin, Raúl Rodríguez‐Cruces, Matthias Kirschner, Gavin P. Winston, Manuela Tondelli, Bradley J. Sinclair, Patricia Desmond, Leon Qi Rong Ooi, Ezequiel L. Gleichgerrcht, Mark P. Richardson, Anna Elisabetta Vaudano, Fernando Cendes, Niels K. Focke, Birgit Frauscher, Antonio Gambardella, Sönke Langner, Leonardo Bonilha, Chantal Depondt, Barbara A. K. Kreilkamp, Tobias Bauer, Mariasavina Severino, Hamid Soltanian‐Zadeh, Roland Wiest, Sara Larivière, Mira Semmelroch, Rhys Huw Thomas, Mario Mascalchi, Lucy Vivash, Luis Concha, Lang Liu, Simon S. Keller, Christopher D. Whelan, Sjoerd B. Vos, Carrie R. McDonald, Neda Bernasconi, Sonya Foley, Sean N. Hatton, Graeme D. Jackson, Sanjay M. Sisodiya, Andrea Bernasconi, Vijay Tiwari, Martin Domín, Alexander Ngo, Elaine Lui, Eric Yu, Angelo Labate, Clarissa Lin Yasuda, Khalid Hamandi, Magdalena Kowalczyk, Valeria Kebets, Felix von Podewills, Ziv Gan‐Or, Theodor Rüber, Serena Fett, Paul M. Thompson, Aditi Singh, Junsong Zhang, Norman Delanty
article en
2 citations

Abstract

Extensive neuroimaging research in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) has identified brain atrophy as a disease phenotype. While it is also related to a complex genetic architecture, the transition from genetic risk factors to brain vulnerabilities remains unclear. Using a population-based approach, we examined the associations between epilepsy-related polygenic risk for HS (PRS-HS) and brain structure in healthy developing children, assessed their relation to brain network architecture, and evaluated its correspondence with case-control findings in TLE-HS diagnosed patients relative to healthy individuals. We used genome-wide genotyping and structural T1-weighted MRI of 3826 neurotypical children from the Adolescent Brain Cognitive Development (ABCD) study. Surface-based linear models related PRS-HS to cortical thickness measures, and subsequently contextualized findings with structural and functional network architecture based on epicentre mapping approaches. Imaging-genetic associations were then correlated to atrophy and disease epicentres in 785 patients with TLE-HS relative to 1512 healthy controls aggregated across multiple sites. Higher PRS-HS was associated with decreases in cortical thickness across temporo-parietal as well as fronto-central regions of neurotypical children. These imaging-genetic effects were anchored to the connectivity profiles of distinct functional and structural epicentres. Compared with disease-related alterations from a separate epilepsy cohort, regional and network correlates of PRS-HS strongly mirrored cortical atrophy and disease epicentres observed in patients with TLE-HS and were highly replicable across different studies. Findings were consistent when using statistical models controlling for spatial autocorrelations and robust to variations in analytic methods. Capitalizing on recent imaging-genetic initiatives, our study provides novel insights into the genetic underpinnings of structural alterations in TLE-HS, revealing common morphological and network pathways between genetic vulnerability and disease mechanisms. These signatures offer a foundation for early risk stratification and personalized interventions targeting genetic profiles in epilepsy.

BrainVol. 149(2)
University of Southern California (US), University of Modena and Reggio Emilia (IT), Montreal Neurological Institute and Hospital (CA), The Royal Melbourne Hospital (AU), Université de Sherbrooke (CA), University of Bonn (DE), University of Liverpool (GB), Emory University (US), Medical University of South Carolina (US), Henry Ford Health System (US), University of South Carolina (US), Autonomous University of Queretaro (MX), National University of Singapore (SG), Duke University (US), Forschungszentrum Jülich (DE), University of Eastern Finland (FI), University of Southern Denmark (DK), Universidade Estadual de Campinas (UNICAMP) (BR), University of Zurich (CH), Queen's University (CA), University of Tehran (IR), University Hospital Bonn (DE), University Hospital of Wales (GB), University Hospital of Bern (CH), Istituto Giannina Gaslini (IT), German Center for Neurodegenerative Diseases (DE), Centre Hospitalier Universitaire de Sherbrooke (CA), The Alfred Hospital (AU), Walton Centre (GB), Epilepsy Research UK (GB), University of California San Diego (US), Magna Graecia University (IT), Monash Alfred Psychiatry Research centre (AU), University Hospital of Zurich (CH), Meyer Children's Hospital (IL), University Hospital of Geneva (CH), Azienda Ospedaliero-Universitaria di Modena (IT), Meyer Children's Hospital (IT), Universitätsmedizin Göttingen (DE), McGill Genome Centre (CA), Azienda Ospedaliera Universitaria Senese (IT), Hertie Institute for Clinical Brain Research (DE), National Hospital for Neurology and Neurosurgery (GB), Epilepsy Foundation (AU), University Psychiatric Hospital (SI), University of Florence (IT), University College London (GB), Epilepsy Society (GB), McGill University (CA), Monash University (AU), New York University (US), Geneva College (US), University of Göttingen (DE), Cardiff University (GB), University of Tübingen (DE), Nanjing Medical University (CN), University of Genoa (IT), Universidad Nacional Autónoma de México (MX), University of Lübeck (DE)
National Science Foundation, National University of Singapore, National Natural Science Foundation of China, China Postdoctoral Science Foundation, Canadian Institutes of Health Research, Fonds de Recherche du Québec - Santé, Medical Research Council, National Medical Research Council
Openalex Percentile: Top 9%
Functional Brain Connectivity Studies
2.86
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