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[Preprint]. 2025 Jan 17:2025.01.17.633277.

doi: 10.1101/2025.01.17.633277.

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

10}, Birgit Frauscher^{11

12}, Casey Paquola¹³, Maria Eugenia Caligiuri¹⁴, Antonio Gambardella¹⁵, Luis Concha¹⁶, Simon S Keller^{17

18}, Fernando Cendes¹⁹, Clarissa L Yasuda¹⁹, Leonardo Bonilha²⁰, Ezequiel Gleichgerrcht²¹, Niels K Focke²², Raviteja Kotikalapudi²³, Terence J O'Brien^{24

25}, Benjamin Sinclair^{24

25}, Lucy Vivash^{24

25}, Patricia M Desmond²⁵, Elaine Lui²⁵, Anna Elisabetta Vaudano^{26

27}, Stefano Meletti^{26

27}, Reetta Kälviäinen^{28

29}, Hamid Soltanian-Zadeh^{30

31}, Gavin P Winston^{32

33

34}, Vijay K Tiwari³⁵, Barbara A K Kreilkamp²², Matteo Lenge^{36

37}, Renzo Guerrini³⁶, Khalid Hamandi^{38

39}, Theodor Rüber^{40

41

42}, Tobias Bauer^{40

41

42}, Orrin Devinsky⁴³, Pasquale Striano^{44

45}, Erik Kaestner⁴⁶, Sean N Hatton⁴⁷, Lorenzo Caciagli^{33

48}, Matthias Kirschner^{49

50}, John S Duncan^{33

34}, Paul M Thompson⁵¹; ENIGMA Consortium Epilepsy Working Group; Carrie R McDonald^{46

52}, Sanjay M Sisodiya^{33

34}, Neda Bernasconi^{1

2}, Andrea Bernasconi^{1

2}, Ziv Gan-Or^{1

2

3}, Boris C Bernhardt^{1

2}

Affiliations

¹ Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
² Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Cabada.
³ Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
⁴ Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Québec, Canada.
⁵ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
⁶ Centre of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.
⁷ Department of Medical Imaging, Nanjing University School of Medicine, Nanjing, China.
⁸ Centre for Sleep and Cognition, National University of Singapore, Singapore, Singapore.
⁹ Centre for Translational Magnetic Resonance, National University of Singapore, Singapore, Singapore.
¹⁰ Department of Electrical and Computer Engineering, National University of Singapore, Singapore, Singapore.
¹¹ Department of Neurology, Duke University, Durham, United States.
¹² Department of Biomedical Engineering, Duke University, Durham, United States.
¹³ Institute of Neuroscience and Medicine (INM-7), Forschungszentrum Ju lich, Ju lich, Germany.
¹⁴ Neuroscience Research Center, University Magna Græcia, Catanzaro, Italy.
¹⁵ Institute of Neurology, University Magna Græcia, Catanzaro, Italy.
¹⁶ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México.
¹⁷ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
¹⁸ Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
¹⁹ Department of Neurology, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
²⁰ Department of Neurology, Emory University, Atlanta, United States.
²¹ Department of Neurology, Medical University of South Carolina, Charleston, SC, USA.
²² Department of Neurology, University of Medicine Göttingen, Göttingen, Germany.
²³ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁴ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Melbourne, Australia.
²⁵ Departments of Medicine and Radiology, The Royal Melbourne Hospital, University of Melbourne, Parkville, Australia.
²⁶ Neurology Unit, OCB Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.
²⁷ Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, Italy.
²⁸ Epilepsy Center, Neuro Center, Kuopio University Hospital, Member of the European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, Finland.
²⁹ Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
³⁰ Control and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, Iran.
³¹ Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, United States.
³² Division of Neurology, Department of Medicine, Queen's University, Kingston, Ontario, Canada.
³³ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.
³⁴ Chalfont Centre for Epilepsy, Bucks, United Kingdom.
³⁵ Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast, Belfast, United Kingdom.
³⁶ Child Neurology Unit and Laboratories, Neuroscience Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
³⁷ Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
³⁸ The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Whales, Cardiff, United Kingdom.
³⁹ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical Sciences, Cardiff University, Cardiff, United Kingdom.
⁴⁰ Department of Epileptology, University of Bonn Medical Center, Bonn, Germany.
⁴¹ Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.
⁴² Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany.
⁴³ Department of Neurology, NYU Grossman School of Medicine, New York, United States.
⁴⁴ IRCCS Istituto Giannina Gaslini, Genova, Italy.
⁴⁵ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.
⁴⁶ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, United States.
⁴⁷ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, United States.
⁴⁸ Department of Neurology, Inselspital, Sleep-Wake-Epilepsy-Center, Bern University Hospital, University of Bern, Bern, Switzerland.
⁴⁹ Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Zurich, Switzerland.
⁵⁰ Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
⁵¹ Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, United States.
⁵² Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, United States.

PMID: 39868179
PMCID: PMC11760683
DOI: 10.1101/2025.01.17.633277

ASSOCIATIONS BETWEEN EPILEPSY-RELATED POLYGENIC RISK AND BRAIN MORPHOLOGY IN CHILDHOOD

Alexander Ngo et al. bioRxiv. 2025.

[Preprint]. 2025 Jan 17:2025.01.17.633277.

doi: 10.1101/2025.01.17.633277.

Authors

Affiliations

¹ Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
² Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Cabada.
³ Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
⁴ Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Québec, Canada.
⁵ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
⁶ Centre of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.
⁷ Department of Medical Imaging, Nanjing University School of Medicine, Nanjing, China.
⁸ Centre for Sleep and Cognition, National University of Singapore, Singapore, Singapore.
⁹ Centre for Translational Magnetic Resonance, National University of Singapore, Singapore, Singapore.
¹⁰ Department of Electrical and Computer Engineering, National University of Singapore, Singapore, Singapore.
¹¹ Department of Neurology, Duke University, Durham, United States.
¹² Department of Biomedical Engineering, Duke University, Durham, United States.
¹³ Institute of Neuroscience and Medicine (INM-7), Forschungszentrum Ju lich, Ju lich, Germany.
¹⁴ Neuroscience Research Center, University Magna Græcia, Catanzaro, Italy.
¹⁵ Institute of Neurology, University Magna Græcia, Catanzaro, Italy.
¹⁶ Institute of Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México.
¹⁷ Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
¹⁸ Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
¹⁹ Department of Neurology, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
²⁰ Department of Neurology, Emory University, Atlanta, United States.
²¹ Department of Neurology, Medical University of South Carolina, Charleston, SC, USA.
²² Department of Neurology, University of Medicine Göttingen, Göttingen, Germany.
²³ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁴ Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, Melbourne, Australia.
²⁵ Departments of Medicine and Radiology, The Royal Melbourne Hospital, University of Melbourne, Parkville, Australia.
²⁶ Neurology Unit, OCB Hospital, Azienda Ospedaliera-Universitaria, Modena, Italy.
²⁷ Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, Italy.
²⁸ Epilepsy Center, Neuro Center, Kuopio University Hospital, Member of the European Reference Network for Rare and Complex Epilepsies EpiCARE, Kuopio, Finland.
²⁹ Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
³⁰ Control and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, University of Tehran, Tehran, Iran.
³¹ Departments of Research Administration and Radiology, Henry Ford Health System, Detroit, United States.
³² Division of Neurology, Department of Medicine, Queen's University, Kingston, Ontario, Canada.
³³ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom.
³⁴ Chalfont Centre for Epilepsy, Bucks, United Kingdom.
³⁵ Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast, Belfast, United Kingdom.
³⁶ Child Neurology Unit and Laboratories, Neuroscience Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
³⁷ Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
³⁸ The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Whales, Cardiff, United Kingdom.
³⁹ Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical Sciences, Cardiff University, Cardiff, United Kingdom.
⁴⁰ Department of Epileptology, University of Bonn Medical Center, Bonn, Germany.
⁴¹ Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.
⁴² Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany.
⁴³ Department of Neurology, NYU Grossman School of Medicine, New York, United States.
⁴⁴ IRCCS Istituto Giannina Gaslini, Genova, Italy.
⁴⁵ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.
⁴⁶ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, United States.
⁴⁷ Department of Neurosciences, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, United States.
⁴⁸ Department of Neurology, Inselspital, Sleep-Wake-Epilepsy-Center, Bern University Hospital, University of Bern, Bern, Switzerland.
⁴⁹ Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Zurich, Switzerland.
⁵⁰ Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
⁵¹ Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, United States.
⁵² Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, United States.

PMID: 39868179
PMCID: PMC11760683
DOI: 10.1101/2025.01.17.633277

Update in

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, Yeo BTT, 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. Brain. 2025 Aug 14:awaf259. doi: 10.1093/brain/awaf259. Online ahead of print. Brain. 2025. PMID: 40811581

Abstract

Temporal 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.

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

PubMed Disclaimer

Conflict of interest statement

POTENTIAL CONFLICTS OF INTEREST All authors declare no competing conflicts of interest.

Figures

**Figure 1 |. PRS-HS associations with cortical thickness (ABCD).**
**(A)** Distribution of genetic risk effects on morphology across the different lobes (in order from top to bottom: all, frontal, limbic, occipital, parietal, temporal). **(B)** Regional imaging-genetic correlations between PRS-HS and thickness. Blue and red colours represent negative and positive correlations, respectively. White outline indicates p_FDR < 0.05. L, left; PRS-HS; polygenic risk score for epilepsy-related hippocampal sclerosis; R, right.

**Figure 2 |. Network epicentres of morphological changes associated with PRS-HS.**
**(A)** Schematic representation of epicentre mapping approach using seed-based cortico- and subcortico-cortical connectivity. PRS-HS, polygenic risk score for epilepsy-related hippocampal sclerosis. **(B)** Correlation coefficients indexing spatial similarity between imaging-genetic effects and seed-based functional (*top*) and structural (*bottom*) connections for every cortical and subcortical region. Red and blue colours represent negative associations, while grey depicts positive correlations. White outline indicates p_spin < 0.05. L, left; R, right.

**Figure 3 |. Comparison between PRS-HS effects and epilepsy case-control atrophy.**
**(A)** Case-control differences in left and right TLE-HS from ENIGMA-Epilepsy (*top*) and from MICs and NKG (*bottom*). Blue and red colours point to atrophy and hypertrophy in patients relative to healthy controls, respectively. Outline in white represents p_FDR < 0.05. L, left; R, right; TLE-HS, temporal lobe epilepsy with hippocampal sclerosis. **(B)** Spatial correlations between epilepsy-related atrophy (*top*: ENIGMA-Epilepsy; *bottom*: MICs and NKG) and imaging-genetic effect maps (ABCD) are compared against permutation-based null correlations. Points represent the empirical correlation (with significance defined as p_spin < 0.05). In the boxplots, the ends of boxes represent the first (25%) and third (75%) quartiles, the centre line (median) represents the second quartile of the null distribution (n = 5,000 permutations), the whiskers represent the non-outlier endpoints of the distribution.

**Figure 4 |. Comparison between imaging-genetic and epilepsy-related disease epicentres.**
**(A)** Functional and structural disease epicentres in left and right TLE-HS from ENIGMA-Epilepsy (*top*) and from MICs and NKG (*bottom*). Red and blue colours represent negative associations, while grey depicts positive correlations. Outline in white represents p_spin < 0.05. L, left; R, right; TLE-HS, temporal lobe epilepsy with hippocampal sclerosis. **(B)** Spatial correlations between epilepsy-related epicentres (*top*: ENIGMA-Epilepsy; *bottom*: MICs and NKG) and imaging-genetic effect maps (ABCD) are compared against permutation-based null correlations. Points represent the empirical correlation (with significance defined as p_spin < 0.05). In the boxplots, the ends of boxes represent the first (25%) and third (75%) quartiles, the centre line (median) represents the second quartile of the null distribution (n = 5,000 permutations), the whiskers represent the non-outlier endpoints of the distribution.

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References

1. Feigin V. L. et al. The global burden of neurological disorders: translating evidence into policy. Lancet Neurol. 19, 255–265 (2020). - PMC - PubMed
1. Epilepsy C. by H.-G W. for the I. C. on N. of. Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis. Epilepsia 45, 695–714 (2004). - PubMed
1. Lin J. J. et al. Reduced Neocortical Thickness and Complexity Mapped in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis. Cereb. Cortex 17, 2007–2018 (2007). - PubMed
1. Keller S. S. & Roberts N. Voxel-based morphometry of temporal lobe epilepsy: An introduction and review of the literature. Epilepsia 49, 741–757 (2008). - PubMed
1. McDonald C. R. et al. Regional neocortical thinning in mesial temporal lobe epilepsy. Epilepsia 49, 794–803 (2008). - PubMed

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This is a preprint.

ASSOCIATIONS BETWEEN EPILEPSY-RELATED POLYGENIC RISK AND BRAIN MORPHOLOGY IN CHILDHOOD

Affiliations

ASSOCIATIONS BETWEEN EPILEPSY-RELATED POLYGENIC RISK AND BRAIN MORPHOLOGY IN CHILDHOOD

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

Figures

References

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