Associations between epilepsy-related polygenic risk and brain morphology in childhood.
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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 B T 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 N, 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 A K, 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
Аннотация
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.