Journal Article

DZNE-2026-00165

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Associations between epilepsy-related polygenic risk and brain morphology in childhood.

Ngo, A. ; Liu, L. ; Larivière, S. ; Kebets, V. ; Fett, S. ; Weber, C. F. ; Royer, J. ; Yu, E. ; Rodríguez-Cruces, R. ; Zhang, Z. ; Ooi, L. Q. R. ; Yeo, B. T. T. ; Frauscher, B. ; Paquola, C. ; Caligiuri, M. E. ; Gambardella, A. ; Concha, L. ; Keller, S. S. ; Cendes, F. ; Yasuda, C. L. ; Bonilha, L. ; Gleichgerrcht, E. ; Focke, N. K. N. ; Kotikalapudi, R. ; O'Brien, T. J. ; Sinclair, B. ; Vivash, L. ; Desmond, P. M. ; Lui, E. ; Vaudano, A. E. ; Meletti, S. ; Kälviäinen, R. ; Soltanian-Zadeh, H. ; Winston, G. P. ; Tiwari, V. K. ; Kreilkamp, B. A. K. ; Lenge, M. ; Guerrini, R. ; Hamandi, K. ; Rüber, T.DZNE* ; Bauer, T.DZNE* ; Devinsky, O. ; Striano, P. ; Kaestner, E. ; Hatton, S. N. ; Caciagli, L. ; Kirschner, M. ; Duncan, J. S. ; Thompson, P. M. ; Group, E. C. E. W. (Collaboration Author) ; McDonald, C. R. ; Sisodiya, S. M. ; Bernasconi, N. ; Bernasconi, A. ; Gan-Or, Z. ; Bernhardt, B. C. ; Abela, E. (Contributor) ; Absil, J. (Contributor) ; Alhusaini, S. (Contributor) ; Carr, S. J. A. (Contributor) ; Cavalleri, G. L. (Contributor) ; Davoodi-Bojd, E. (Contributor) ; Delanty, N. (Contributor) ; Depondt, C. (Contributor) ; Doherty, C. P. (Contributor) ; Domin, M. (Contributor) ; Foley, S. (Contributor) ; Griffin, A. (Contributor) ; Jackson, G. D. (Contributor) ; Kowalczyk, M. (Contributor) ; Labate, A. (Contributor) ; Langner, S. (Contributor) ; Mascalchi, M. (Contributor) ; Martin, P. (Contributor) ; Richardson, M. P. (Contributor) ; Rummel, C. (Contributor) ; Semmelroch, M. (Contributor) ; Severino, M. (Contributor) ; Singh, A. (Contributor) ; Thomas, R. H. (Contributor) ; Tondelli, M. (Contributor) ; Tortora, D. (Contributor) ; von Podewills, F. (Contributor) ; Vos, S. B. (Contributor) ; Whelan, C. D. (Contributor) ; Wiest, R. (Contributor) ; Zhang, J. (Contributor)

2026
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awaf259

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.

Keyword(s): Humans (MeSH) ; Male (MeSH) ; Female (MeSH) ; Child (MeSH) ; Adolescent (MeSH) ; Multifactorial Inheritance: genetics (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Brain: pathology (MeSH) ; Brain: diagnostic imaging (MeSH) ; Epilepsy, Temporal Lobe: genetics (MeSH) ; Epilepsy, Temporal Lobe: pathology (MeSH) ; Epilepsy, Temporal Lobe: diagnostic imaging (MeSH) ; Atrophy (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Genome-Wide Association Study (MeSH) ; Hippocampus: pathology (MeSH) ; Hippocampus: diagnostic imaging (MeSH) ; Epilepsy: genetics (MeSH) ; Epilepsy: pathology (MeSH) ; Epilepsy: diagnostic imaging (MeSH) ; Case-Control Studies (MeSH) ; Sclerosis: pathology (MeSH) ; Risk Factors (MeSH) ; brain structure ; childhood ; genetic risk ; imaging-genetics ; temporal lobe epilepsy

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Contributing Institute(s):

1. MR Physics (AG Stöcker)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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