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

Alexander Ngo^{1

2}, Lang Liu^{1

3}, Sara Larivière⁴, Valeria Kebets^{1

2}, Serena Fett^{1

2}, Clara F Weber^{1

5

6}, Jessica Royer^{1

2}, Eric Yu^{1

3}, Raúl Rodríguez-Cruces^{1

2}, Zhiqiang Zhang⁷, Leon Qi Rong Ooi^{8

9

10}, B T Thomas Yeo^{8

9

11}, Birgit Frauscher^{12

13}, Casey Paquola¹⁴, Maria Eugenia Caligiuri¹⁵, Antonio Gambardella¹⁶, Luis Concha¹⁷, Simon S Keller^{18

19}, Fernando Cendes²⁰, Clarissa L Yasuda²⁰, Leonardo Bonilha²¹, Ezequiel Gleichgerrcht²², Niels K Focke²³, Raviteja Kotikalapudi²⁴, Terence J O'Brien^{25

26}, Benjamin Sinclair^{25

26}, Lucy Vivash^{25

26}, Patricia M Desmond²⁶, Elaine Lui²⁶, Anna Elisabetta Vaudano^{27

28}, Stefano Meletti^{27

28}, Reetta Kälviäinen^{29

30}, Hamid Soltanian-Zadeh^{31

32}, Gavin P Winston^{33

34

35}, Vijay K Tiwari³⁶, Barbara A K Kreilkamp²³, Matteo Lenge³⁷, Renzo Guerrini^{37

38}, Khalid Hamandi^{39

40}, Theodor Rüber^{41

42

43

44}, Tobias Bauer^{41

42

43}, Orrin Devinsky⁴⁵, Pasquale Striano⁴⁶, Erik Kaestner⁴⁷, Sean N Hatton⁴⁸, Lorenzo Caciagli^{33

49}, Matthias Kirschner^{50

51}, John S Duncan^{33

34}, Paul M Thompson⁵²; ENIGMA Consortium Epilepsy Working Group; Carrie R McDonald^{47

53}, Sanjay M Sisodiya^{33

34}, Neda Bernasconi^{1

2}, Andrea Bernasconi^{1

2}, Ziv Gan-Or^{1

2

3}, Boris C Bernhardt^{1

2}

Collaborators, Affiliations

Collaborators

Affiliations

¹ Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, H3A 2B4, Canada.
² Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 1A1, Canada.
³ Department of Human Genetics, McGill University, Montreal, QC, H3A 1Y2, Canada.
⁴ Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.
⁵ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, 23538, Germany.
⁶ Centre of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, 23562, Germany.
⁷ Department of Medical Imaging, Nanjing University School of Medicine, Nanjing, 211166, China.
⁸ Centre for Sleep and Cognition, National University of Singapore, Singapore, 117549 Singapore.
⁹ Centre for Translational Magnetic Resonance, National University of Singapore, Singapore, 117549, Singapore.
¹⁰ Department of Electrical and Computer Engineering, National University of Singapore, Singapore, 117583, Singapore.
¹¹ ssDepartment of Electrical and Computer Engineering, National University of Singapore, Singapore, 117583, Singapore.
¹² Department of Neurology, Duke University, Durham, NC, 27710, USA.
¹³ Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
¹⁴ Institute of Neuroscience and Medicine (INM-7), Forschungszentrum Jülich, Jülich, 52428, Germany.
¹⁵ Neuroscience Research Center, University Magna Græcia, Catanzaro, 88100, Italy.
¹⁶ Institute of Neurology, University Magna Græcia, Catanzaro, 88100, Italy.
¹⁷ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, 76230, México.
¹⁸ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7BE, UK.
¹⁹ Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, UK.
²⁰ Department of Neurology, University of Campinas-UNICAMP, Campinas, São Paulo, 13083887, Brazil.
²¹ Department of Neurology, Emory University, Atlanta, GA, 30322, USA.
²² Department of Neurology, Medical University of South Carolina, Charleston, SC, 29425, USA.
²³ Department of Neurology, University of Medicine Göttingen, Göttingen, 37075, Germany.
²⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
²⁵ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Melbourne, VIC, 3004, Australia.
²⁶ Departments of Medicine and Radiology, The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, 3050, Australia.
²⁷ Neurology Unit, OCB Hospital, Azienda Ospedaliera-Universitaria, Modena, 41126, Italy.
²⁸ Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, 41125, Italy.
²⁹ Epilepsy Center, Neuro Center, Kuopio University Hospital, Member of the European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, 70210, Finland.
³⁰ Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, 70210, Finland.
³¹ Control and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, 1439957131, Iran.
³² Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, 48202, USA.
³³ Division of Neurology, Department of Medicine, Queen's University, Kingston, ON, K7L 2V7, Canada.
³⁴ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
³⁵ Chalfont Centre for Epilepsy, Bucks, SL9 0RJ, UK.
³⁶ Institute for Molecular Medicine, University of Southern Denmark, Odense, s5230 Denmark.
³⁷ Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, 50139, Italy.
³⁸ University of Florence, Florence, 50121, Italy.
³⁹ The Wales Epilepsy Unit, Department of Neurology, University Hospital of Whales, Cardiff, CF14 4XW, UK.
⁴⁰ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
⁴¹ Department of Epileptology, University of Bonn Medical Center, Bonn, 53127, Germany.
⁴² Department of Neuroradiology, University of Bonn Medical Center, Bonn, 53127, Germany.
⁴³ German Center for Neurodegenerative Diseases, Göttingen, 37075, Germany.
⁴⁴ Center for Medical Data Usability and Translation, University of Bonn, Bonn, 53113, Germany.
⁴⁵ Department of Neurology, NYU Grossman School of Medicine, New York, NY, 10017, USA.
⁴⁶ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, 16147, Italy.
⁴⁷ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
⁴⁸ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, 92093, USA.
⁴⁹ Department of Neurology, Inselspital, Sleep-Wake-Epilepsy-Center, Bern University Hospital, University of Bern, Bern, 3010, Switzerland.
⁵⁰ Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Zurich, 8008, Switzerland.
⁵¹ Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, 1205, Switzerland.
⁵² Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁵³ Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, 92093, USA.

PMID: 40811581
DOI: 10.1093/brain/awaf259

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

Alexander Ngo et al. Brain. 2025.

. 2025 Aug 14:awaf259.

doi: 10.1093/brain/awaf259. Online ahead of print.

Authors

Collaborators

Affiliations

¹ Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, H3A 2B4, Canada.
² Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 1A1, Canada.
³ Department of Human Genetics, McGill University, Montreal, QC, H3A 1Y2, Canada.
⁴ Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.
⁵ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, 23538, Germany.
⁶ Centre of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, 23562, Germany.
⁷ Department of Medical Imaging, Nanjing University School of Medicine, Nanjing, 211166, China.
⁸ Centre for Sleep and Cognition, National University of Singapore, Singapore, 117549 Singapore.
⁹ Centre for Translational Magnetic Resonance, National University of Singapore, Singapore, 117549, Singapore.
¹⁰ Department of Electrical and Computer Engineering, National University of Singapore, Singapore, 117583, Singapore.
¹¹ ssDepartment of Electrical and Computer Engineering, National University of Singapore, Singapore, 117583, Singapore.
¹² Department of Neurology, Duke University, Durham, NC, 27710, USA.
¹³ Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
¹⁴ Institute of Neuroscience and Medicine (INM-7), Forschungszentrum Jülich, Jülich, 52428, Germany.
¹⁵ Neuroscience Research Center, University Magna Græcia, Catanzaro, 88100, Italy.
¹⁶ Institute of Neurology, University Magna Græcia, Catanzaro, 88100, Italy.
¹⁷ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, 76230, México.
¹⁸ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7BE, UK.
¹⁹ Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, UK.
²⁰ Department of Neurology, University of Campinas-UNICAMP, Campinas, São Paulo, 13083887, Brazil.
²¹ Department of Neurology, Emory University, Atlanta, GA, 30322, USA.
²² Department of Neurology, Medical University of South Carolina, Charleston, SC, 29425, USA.
²³ Department of Neurology, University of Medicine Göttingen, Göttingen, 37075, Germany.
²⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
²⁵ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Melbourne, VIC, 3004, Australia.
²⁶ Departments of Medicine and Radiology, The Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, 3050, Australia.
²⁷ Neurology Unit, OCB Hospital, Azienda Ospedaliera-Universitaria, Modena, 41126, Italy.
²⁸ Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, 41125, Italy.
²⁹ Epilepsy Center, Neuro Center, Kuopio University Hospital, Member of the European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, 70210, Finland.
³⁰ Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, 70210, Finland.
³¹ Control and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, 1439957131, Iran.
³² Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, 48202, USA.
³³ Division of Neurology, Department of Medicine, Queen's University, Kingston, ON, K7L 2V7, Canada.
³⁴ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
³⁵ Chalfont Centre for Epilepsy, Bucks, SL9 0RJ, UK.
³⁶ Institute for Molecular Medicine, University of Southern Denmark, Odense, s5230 Denmark.
³⁷ Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS, Florence, 50139, Italy.
³⁸ University of Florence, Florence, 50121, Italy.
³⁹ The Wales Epilepsy Unit, Department of Neurology, University Hospital of Whales, Cardiff, CF14 4XW, UK.
⁴⁰ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
⁴¹ Department of Epileptology, University of Bonn Medical Center, Bonn, 53127, Germany.
⁴² Department of Neuroradiology, University of Bonn Medical Center, Bonn, 53127, Germany.
⁴³ German Center for Neurodegenerative Diseases, Göttingen, 37075, Germany.
⁴⁴ Center for Medical Data Usability and Translation, University of Bonn, Bonn, 53113, Germany.
⁴⁵ Department of Neurology, NYU Grossman School of Medicine, New York, NY, 10017, USA.
⁴⁶ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, 16147, Italy.
⁴⁷ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
⁴⁸ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, 92093, USA.
⁴⁹ Department of Neurology, Inselspital, Sleep-Wake-Epilepsy-Center, Bern University Hospital, University of Bern, Bern, 3010, Switzerland.
⁵⁰ Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Zurich, 8008, Switzerland.
⁵¹ Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, 1205, Switzerland.
⁵² Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁵³ Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, 92093, USA.

PMID: 40811581
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 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.

Keywords: brain structure; childhood; genetic risk; imaging-genetics; temporal lobe epilepsy.

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ASSOCIATIONS BETWEEN EPILEPSY-RELATED POLYGENIC RISK AND BRAIN MORPHOLOGY IN CHILDHOOD.
Ngo A, Liu L, Larivière S, Kebets V, Fett S, Weber CF, Royer J, Yu E, Rodríguez-Cruces R, Zhang Z, Ooi LQR, Thomas Yeo BT, Frauscher B, Paquola C, Caligiuri ME, Gambardella A, Concha L, Keller SS, Cendes F, Yasuda CL, Bonilha L, Gleichgerrcht E, Focke NK, Kotikalapudi R, O'Brien TJ, Sinclair B, Vivash L, Desmond PM, Lui E, Vaudano AE, Meletti S, Kälviäinen R, Soltanian-Zadeh H, Winston GP, Tiwari VK, Kreilkamp BAK, Lenge M, Guerrini R, Hamandi K, Rüber T, Bauer T, Devinsky O, Striano P, Kaestner E, Hatton SN, Caciagli L, Kirschner M, Duncan JS, Thompson PM; ENIGMA Consortium Epilepsy Working Group; McDonald CR, Sisodiya SM, Bernasconi N, Bernasconi A, Gan-Or Z, Bernhardt BC. Ngo A, et al. bioRxiv [Preprint]. 2025 Jan 17:2025.01.17.633277. doi: 10.1101/2025.01.17.633277. bioRxiv. 2025. Update in: Brain. 2025 Aug 14:awaf259. doi: 10.1093/brain/awaf259. PMID: 39868179 Free PMC article. Updated. Preprint.

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Update of

LinkOut - more resources

Full Text Sources