Ngo, Alexander; Liu, Lang; Larivière, Sara; Kebets, Valeria; Fett, Serena; Weber, Clara F; Royer, Jessica; ... Bernhardt, Boris C; + view all Ngo, Alexander; Liu, Lang; Larivière, Sara; Kebets, Valeria; Fett, Serena; Weber, Clara F; Royer, Jessica; Yu, Eric; Rodríguez-Cruces, Raúl; Zhang, Zhiqiang; Ooi, Leon Qi Rong; Yeo, BT Thomas; Frauscher, Birgit; Paquola, Casey; Caligiuri, Maria Eugenia; Gambardella, Antonio; Concha, Luis; Keller, Simon S; Cendes, Fernando; Yasuda, Clarissa L; Bonilha, Leonardo; Gleichgerrcht, Ezequiel; Focke, Niels K; Kotikalapudi, Raviteja; O'Brien, Terence J; Sinclair, Benjamin; Vivash, Lucy; Desmond, Patricia M; Lui, Elaine; Vaudano, Anna Elisabetta; Meletti, Stefano; Kälviäinen, Reetta; Soltanian-Zadeh, Hamid; Winston, Gavin P; Tiwari, Vijay K; Kreilkamp, Barbara AK; Lenge, Matteo; Guerrini, Renzo; Hamandi, Khalid; Rüber, Theodor; Bauer, Tobias; Devinsky, Orrin; Striano, Pasquale; Kaestner, Erik; Hatton, Sean N; Caciagli, Lorenzo; Kirschner, Matthias; Duncan, John S; Thompson, Paul M; ENIGMA Consortium Epilepsy Working Group, .; McDonald, Carrie R; Sisodiya, Sanjay M; Bernasconi, Neda; Bernasconi, Andrea; Gan-Or, Ziv; Bernhardt, Boris C; - view fewer (2025) Associations between epilepsy-related polygenic risk and brain morphology in childhood. Brain , Article awaf259. 10.1093/brain/awaf259.

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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 magnetic resonance imaging (MRI) of 3,826 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 1,512 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 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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