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

Alexander Ngo; Lang Liu; Sara Larivière; Valeria Kebets; Serena Fett; Clara F. Weber; Jessica Royer; Eric Yu; Raúl Rodríguez‐Cruces; Zhiqiang Zhang; Leon Qi Rong Ooi; B.T. Thomas Yeo; Birgit Frauscher; Casey Paquola; Maria Eugenia Caligiuri; Antonio Gambardella; Luis Concha; Simon Sean Keller; Fernando Cendes; Clarissa Lin Yasuda; Leonardo Bonilha; Ezequiel L. Gleichgerrcht; Niels K. Focke; Raviteja Kotikalapudi; Terence John O'Brien; Benjamin Sinclair; Lucy E. Vivash; Patricia M. Desmond; ELAINE H. LUI; Anna Elisabetta Vaudano

doi:10.1093/brain/awaf259

NeuroscienceBrainAug 8, 2025

Peer-reviewed journal article

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

Alexander Ngo iD, Lang Liu iD, Sara Larivière iD, Valeria Kebets iD, Serena Fett, Clara F. Weber iD, Jessica Royer iD, Eric Yu iD, Raúl Rodríguez‐Cruces iD, Zhiqiang Zhang iD, Leon Qi Rong Ooi iD, B.T. Thomas Yeo iD, Birgit Frauscher iD, Casey Paquola iD, Maria Eugenia Caligiuri iD, Antonio Gambardella iD, Luis Concha iD, Simon Sean Keller iD, Fernando Cendes iD, Clarissa Lin Yasuda iD, Leonardo Bonilha iD, Ezequiel L. Gleichgerrcht iD, Niels K. Focke iD, Raviteja Kotikalapudi iD, Terence John O'Brien iD, , Boris C. Bernhardt iD

Abstract

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres. Compared to disease-related effects derived from epilepsy case-control cohorts, structural correlates of PRS-HS mirrored atrophy and epicentre patterns in patients with TLE-HS. By identifying a potential pathway between genetic vulnerability and disease mechanisms, our findings provide new insights into the genetic underpinnings of structural alterations in TLE-HS and highlight potential imaging-genetic biomarkers for early risk stratification and personalized interventions.

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