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2. Multimodal wearable EEG, EMG and accelerometry measurements improve the accuracy of tonic-clonic seizure detection in-hospital

Author

Zhang, Jingwei, Swinnen, Lauren, Chatzichristos, Christos, Broux, Victoria, Proost, Renee, Jansen, Katrien, Mahler, Benno, Zabler, Nicolas, Epitashvilli, Nino, Dümpelmann, Matthias, Schulze-Bonhage, Andreas, Schriewer, Elisabeth, Ermis, Ummahan, Wolking, Stefan, Linke, Florian, Weber, Yvonne, Symmonds, Mkael, Sen, Arjune, Biondi, Andrea, Richardson, Mark P., Sulaiman I, Abuhaiba, Silva, Ana Isabel, Sales, Francisco, Vértes, Gergely, Van Paesschen, Wim, and De Vos, Maarten

Subjects
Electrical Engineering and Systems Science - Signal Processing
Abstract

Objective: Most current wearable tonic-clonic seizure (TCS) detection systems are based on extra-cerebral signals, such as electromyography (EMG) or accelerometry (ACC). Although many of these devices show good sensitivity in seizure detection, their false positive rates (FPR) are still relatively high. Wearable EEG may improve performance; however, studies investigating this remain scarce. This paper aims 1) to investigate the possibility of detecting TCSs with a behind-the-ear, two-channel wearable EEG, and 2) to evaluate the added value of wearable EEG to other non-EEG modalities in multimodal TCS detection. Method: We included 27 participants with a total of 44 TCSs from the European multicenter study SeizeIT2. The multimodal wearable detection system Sensor Dot (Byteflies) was used to measure two-channel, behind-the-ear EEG, EMG, electrocardiography (ECG), ACC and gyroscope (GYR). First, we evaluated automatic unimodal detection of TCSs, using performance metrics such as sensitivity, precision, FPR and F1-score. Secondly, we fused the different modalities and again assessed performance. Algorithm-labeled segments were then provided to a neurologist and a wearable data expert, who reviewed and annotated the true positive TCSs, and discarded false positives (FPs). Results: Wearable EEG outperformed the other modalities in unimodal TCS detection by achieving a sensitivity of 100.0% and a FPR of 10.3/24h (compared to 97.7% sensitivity and 30.9/24h FPR for EMG; 95.5% sensitivity and 13.9 FPR for ACC). The combination of wearable EEG and EMG achieved overall the most clinically useful performance in offline TCS detection with a sensitivity of 97.7%, a FPR of 0.4/24 h, a precision of 43.0%, and a F1-score of 59.7%. Subsequent visual review of the automated detections resulted in maximal sensitivity and zero FPs.

Published
2024

8. Modeling Clinical Guidelines for an Epilepsy-CDSS: The EDiTh Project

Author

Pérez Garriga, Ariadna, primary, Wolking, Stefan, additional, Fortmann, Jonas, additional, Majeed, Raphael W., additional, Stockem, Christian, additional, Niekrenz, Lukas, additional, Bosselmann, Christian, additional, Weber, Yvonne, additional, Röhrig, Rainer, additional, and Lipprandt, Myriam, additional

Published
2023
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10. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author

Collaborative, Epi25, Feng, Yen-Chen Anne, Howrigan, Daniel P, Abbott, Liam E, Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L, Dhindsa, Ryan S, Stanley, Kate E, Cavalleri, Gianpiero L, Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M, Cossette, Patrick, Cotsapas, Chris, De Jonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G, Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J, Scheffer, Ingrid E, Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M, Bellows, Susannah T, Leu, Costin, Bennett, Caitlin A, Johns, Esther MC, Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J, Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M, Sadoway, Tara R, Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S, Kousiappa, Ioanna, Tanteles, George A, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S, Knake, Susanne, Kunz, Wolfram S, Zsurka, Gábor, Elger, Christian E, Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D, Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R, Krey, Ilona, Weber, Yvonne G, Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F, Steinhoff, Bernhard J, Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, and Schreiber, Herbert

Subjects
Clinical Research, Human Genome, Neurosciences, Epilepsy, Biotechnology, Genetics, Neurodegenerative, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Case-Control Studies, DNA Mutational Analysis, Exome, Genetic Markers, Genetic Predisposition to Disease, Genetic Variation, Humans, Phenotype, Exome Sequencing, Epi25 Collaborative. Electronic address: s.berkovic@unimelb.edu.au, Epi25 Collaborative, burden analysis, epilepsy, epileptic encephalopathy, exome, seizures, sequencing, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Published
2019

11. Clinical spectrum of STX1B-related epileptic disorders.

Author

Cilio, Maria, Van Paesschen, Wim, Svendsen, Lene, Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Margarita, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair, Vavoulis, Dimitris, Knight, Samantha, Taylor, Jenny, Canevini, Maria, Darra, Francesca, Gavrilova, Ralitza, Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Eric, Kluger, Gerhard, Lowenstein, Daniel, Weckhuysen, Sarah, Pal, Deb, Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys, Rees, Mark, Lesca, Gaetan, Sisodiya, Sanjay, Weber, Yvonne, Lal, Dennis, Marini, Carla, Lerche, Holger, Schubert, Julian, Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke, Balestrini, Simona, Helbig, Katherine, Altuzarra, Cecilia, Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce, and Numis, Adam

Subjects
Adolescent, Anticonvulsants, Child, Child, Preschool, Developmental Disabilities, Drug Resistant Epilepsy, Electroencephalography, Epilepsies, Partial, Epileptic Syndromes, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Learning Disabilities, Loss of Function Mutation, Male, Mutation, Missense, Phenotype, Seizures, Febrile, Sequence Analysis, DNA, Syntaxin 1, Young Adult
Abstract

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Published
2019

14. Multimodal wearable EEG, EMG and accelerometry measurements improve the accuracy of tonic-clonic seizure detection

Author

Zhang, Jingwei, primary, Swinnen, Lauren, additional, Chatzichristos, Christos, additional, Broux, Victoria, additional, Proost, Renee, additional, Jansen, Katrien, additional, Mahler, Benno, additional, Zabler, Nicolas, additional, Epitashvilli, Nino, additional, Duempelmann, Matthias, additional, Schulze-Bonhage, Andreas, additional, Schriewer, Elisabeth, additional, Ermis, Ummahan, additional, Wolking, Stefan, additional, Linke, Florian, additional, Weber, Yvonne, additional, Symmonds, Mkael, additional, Sen, Arjune, additional, Biondi, Andrea, additional, Richardson, Mark P, additional, Sulaiman I, Abuhaiba, additional, Silva, Ana Isabel, additional, Sales, Francisco, additional, Vértes, Gergely, additional, Van Paesschen, Wim, additional, and De Vos, Maarten, additional

Published
2024
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17. Visualising Data Models of Patient Registries and Clinical Studies - A Method for Quality Check of EDC Systems.

Author

COLDEWEY, Beatrice, HONRATH, Philipp, WOLKING, Stefan, NIEMEYER, Anna, RÖHRIG, Rainer, WEBER, Yvonne, and LIPPRANDT, Myriam

Abstract

Introduction: The configuration of electronic data capture (EDC) systems has a relevant impact on data quality in studies and patient registries. The objective was to develop a method to visualise the configuration of an EDC system to check the completeness and correctness of the data definition and rules. Methods: Step 1: transformation of the EDC data model into a graphical model, step 2: Checking the completeness and consistency of the data model, step 3: correction of identified findings. This process model was evaluated on the patient registry EpiReg. Results: Using the graphical visualisation as a basis, 21 problems in the EDC configuration were identified, discussed with an interdisciplinary team, and corrected. Conclusion: The tested methodological approach enables an improvement in data quality by optimising the underlying EDC configuration. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, François, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-François, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Pauls, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L, Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Arfan Ikram, M, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, Sonsma, Anja C.M., Jonghe, Peter De, and Ikram, M Arfan

Published
2018
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20. Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

Author

Mayerhofer, Ernst, Parodi, Livia, Narasimhalu, Kaavya, Wolking, Stefan, Harloff, Andreas, Georgakis, Marios K, Rosand, Jonathan, and Anderson, Christopher D

Subjects
ISCHEMIC stroke, VALPROIC acid, GENETIC variation, PROPORTIONAL hazards models, GENOME-wide association studies
Abstract

Background: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. Aims: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. Methods: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. Results: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). Conclusion: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. Data access statement: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Genetic diagnostics in epilepsies: recommendations of the Commission Epilepsy and Genetics of German Society of Epileptology (German ILAE Chapter)

Author

Boßelmann, Christian, primary, Borggräfe, Ingo, additional, Fazeli, Walid, additional, Klein, Karl-Martin, additional, Kluger, Gerhard J., additional, Müller-Schlüter, Karen, additional, Neubauer, Bernd A., additional, von Spiczak, Sarah, additional, Steinbeis von Stülpnagel, Celina, additional, Weber, Yvonne, additional, Lemke, Johannes R., additional, Wolking, Stefan, additional, and Krey, Ilona, additional

Published
2023
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22. Clinical spectrum of STX1B-related epileptic disorders

Author

Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke S., Balestrini, Simona, Helbig, Katherine L., Altuzarra, Cecilia Desmettre, Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce A., Numis, Adam, Cilio, Maria R., Van Paesschen, Wim, Svendsen, Lene L., Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Margarita, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair T., Vavoulis, Dimitris V., Knight, Samantha J.L., Taylor, Jenny C., Canevini, Maria Paola, Darra, Francesca, Gavrilova, Ralitza H., Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Eric W., Kluger, Gerhard J., Lowenstein, Daniel H., Weckhuysen, Sarah, Pal, Deb K., Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys H., Rees, Mark I., Lesca, Gaetan, Sisodiya, Sanjay M., Weber, Yvonne G., Lal, Dennis, Marini, Carla, Lerche, Holger, and Schubert, Julian

Published
2019
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25. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Author

McCormack, Mark, Gui, Hongsheng, Ingason, Andrés, Speed, Doug, Wright, Galen E.B., Zhang, Eunice J., Secolin, Rodrigo, Yasuda, Clarissa, Kwok, Maxwell, Wolking, Stefan, Becker, Felicitas, Rau, Sarah, Avbersek, Andreja, Heggeli, Kristin, Leu, Costin, Depondt, Chantal, Sills, Graeme J., Marson, Anthony G., Auce, Pauls, Brodie, Martin J., Francis, Ben, Johnson, Michael R., Koeleman, Bobby P.C., Striano, Pasquale, Coppola, Antonietta, Zara, Federico, Kunz, Wolfram S., Sander, Josemir W., Lerche, Holger, Klein, Karl Martin, Weckhuysen, Sarah, Krenn, Martin, Gudmundsson, Lárus J., Stefánsson, Kári, Krause, Roland, Shear, Neil, Ross, Colin J.D., Delanty, Norman, Pirmohamed, Munir, Carleton, Bruce C., Cendes, Fernando, Lopes-Cendes, Iscia, Liao, Wei-ping, OʼBrien, Terence J., Sisodiya, Sanjay M., Cherny, Stacey, Kwan, Patrick, Baum, Larry, and Cavalleri, Gianpiero L.

Published
2018
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27. The role of common genetic variation in presumed monogenic epilepsies

Author

Campbell, Ciarán, Leu, Costin, Feng, Yen-Chen Anne, Wolking, Stefan, Moreau, Claudia, Ellis, Colin, Ganesan, Shiva, Martins, Helena, Oliver, Karen, Boothman, Isabelle, Benson, Katherine, Molloy, Anne, Brody, Lawrence, Michaud, Jacques L., Hamdan, Fadi F., Minassian, Berge A., Lerche, Holger, Scheffer, Ingrid E., Sisodiya, Sanjay, Girard, Simon, Cosette, Patrick, Delanty, Norman, Lal, Dennis, Cavalleri, Gianpiero L., collaborative, Epi K., Consortium, Genomics England Research, Collaborative, The Epi, May, Patrick, Krause, Roland, Fonds National de la Recherche - FnR [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Epilepsy, Neurologie [D14] [Sciences de la santé humaine], Neurology [D14] [Human health sciences], Genetic diagnostics, DEEs, Genetics & genetic processes [F10] [Life sciences], PRS, Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract

Summary: Background The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. Methods: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for ‘all epilepsy’, ‘focal epilepsy’, and ‘genetic generalised epilepsy’ (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. Findings 0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. Interpretation: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders.

Published
2022

30. The role of common genetic variation in presumed monogenic epilepsies

Author

Campbell, Ciarán, primary, Leu, Costin, additional, Feng, Yen-Chen Anne, additional, Wolking, Stefan, additional, Moreau, Claudia, additional, Ellis, Colin, additional, Ganesan, Shiva, additional, Martins, Helena, additional, Oliver, Karen, additional, Boothman, Isabelle, additional, Benson, Katherine, additional, Molloy, Anne, additional, Brody, Lawrence, additional, Michaud, Jacques L., additional, Hamdan, Fadi F., additional, Minassian, Berge A., additional, Lerche, Holger, additional, Scheffer, Ingrid E., additional, Sisodiya, Sanjay, additional, Girard, Simon, additional, Cosette, Patrick, additional, Delanty, Norman, additional, Lal, Dennis, additional, and Cavalleri, Gianpiero L., additional

Published
2022
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31. The role of common genetic variation in presumed monogenic epilepsies

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Campbell, Ciarán, Leu, Costin, Feng, Yen-Chen Anne, Wolking, Stefan, Moreau, Claudia, Ellis, Colin, Ganesan, Shiva, Martins, Helena, Oliver, Karen, Boothman, Isabelle, Benson, Katherine, Molloy, Anne, Brody, Lawrence, Michaud, Jacques L., Hamdan, Fadi F., Minassian, Berge A., Lerche, Holger, Scheffer, Ingrid E., Sisodiya, Sanjay, Girard, Simon, Cosette, Patrick, Delanty, Norman, Lal, Dennis, Cavalleri, Gianpiero L., collaborative, Epi K., Consortium, Genomics England Research, Collaborative, The Epi, May, Patrick, Krause, Roland, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Campbell, Ciarán, Leu, Costin, Feng, Yen-Chen Anne, Wolking, Stefan, Moreau, Claudia, Ellis, Colin, Ganesan, Shiva, Martins, Helena, Oliver, Karen, Boothman, Isabelle, Benson, Katherine, Molloy, Anne, Brody, Lawrence, Michaud, Jacques L., Hamdan, Fadi F., Minassian, Berge A., Lerche, Holger, Scheffer, Ingrid E., Sisodiya, Sanjay, Girard, Simon, Cosette, Patrick, Delanty, Norman, Lal, Dennis, Cavalleri, Gianpiero L., collaborative, Epi K., Consortium, Genomics England Research, Collaborative, The Epi, May, Patrick, and Krause, Roland

Abstract

Summary: Background The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. Methods: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for ‘all epilepsy’, ‘focal epilepsy’, and ‘genetic generalised epilepsy’ (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. Findings 0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. Interpretation: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders.

Published
2022

32. Assessment of burden and segregation profiles of CNVs in patients with epilepsy

Author

Moreau, Claudia, Tremblay, Frédérique, Wolking, Stefan, Girard, Alexandre, Laprise, Catherine, Hamdan, Fadi F., Michaud, Jacques L., Minassian, Berge A., Cossette, Patrick, Girard, Simon, Moreau, Claudia, Tremblay, Frédérique, Wolking, Stefan, Girard, Alexandre, Laprise, Catherine, Hamdan, Fadi F., Michaud, Jacques L., Minassian, Berge A., Cossette, Patrick, and Girard, Simon

Abstract

Objective: Microdeletions are associated with different forms of epilepsy but show incomplete penetrance, which is not well understood. We aimed to assess whether unmasked variants or double CNVs could explain incomplete penetrance. Methods: We analyzed copy number variants (CNVs) in 603 patients with four different subgroups of epilepsy and 945 controls. CNVs were called from genotypes and validated on whole-genome (WGS) or whole-exome sequences (WES). CNV burden difference between patients and controls was obtained by fitting a logistic regression. CNV burden was assessed for small and large (>1 Mb) deletions and duplications and for deletions overlapping different gene sets. Results: Large deletions were enriched in genetic generalized epilepsies (GGE) compared to controls. We also found enrichment of deletions in epilepsy genes and hotspots for GGE. We did not find truncating or functional variants that could have been unmasked by the deletions. We observed a double CNV hit in two patients. One patient also carried a de novo deletion in the 22q11.2 hotspot. Interpretation: We could corroborate previous findings of an enrichment of large microdeletions and deletions in epilepsy genes in GGE. We could also replicate that microdeletions show incomplete penetrance. However, we could not validate the hypothesis of unmasked variants nor the hypothesis of double CNVs to explain the incomplete penetrance. We found a de novo CNV on 22q11.2 that could be of interest. We also observed GGE families carrying a deletion on 15q13.3 hotspot that could be investigated in the Quebec founder population.

Published
2022
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33. Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies

Author

Dohrn, Maike F., Glöckle, Nicola, Mulahasanovic, Lejla, Heller, Corina, Mohr, Julia, Bauer, Christine, Riesch, Erik, Becker, Andrea, Battke, Florian, Hörtnagel, Konstanze, Hornemann, Thorsten, Suriyanarayanan, Saranya, Blankenburg, Markus, Schulz, Jörg B., Claeys, Kristl G., Gess, Burkhard, Katona, Istvan, Ferbert, Andreas, Vittore, Debora, Grimm, Alexander, Wolking, Stefan, Schöls, Ludger, Lerche, Holger, Korenke, G. Christoph, Fischer, Dirk, Schrank, Bertold, Kotzaeridou, Urania, Kurlemann, Gerhard, Dräger, Bianca, Schirmacher, Anja, Young, Peter, Schlotter‐Weigel, Beate, and Biskup, Saskia

Published
2017
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34. Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Author

Androsova, Ganna, Krause, Roland, Borghei, Mojgansadat, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Depondt, Chantal, Brodie, Martin J., Chinthapalli, Krishna, de Haan, Gerrit‐Jan, Doherty, Colin, Gudmundsson, Lárus J., Heavin, Sinead, Ingason, Andres, Johnson, Michael, Kennedy, Clare, Krenn, Martin, McCormack, Mark, OʼBrien, Terence J., Pandolfo, Massimo, Pataraia, Ekaterina, Petrovski, Slave, Rau, Sarah, Sargsyan, Narek, Slattery, Lisa, Stefánsson, Kári, Stern, William, Tostevin, Anna, Willis, Joseph, and Zimprich, Fritz

Published
2017
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39. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, Joshua E., primary, Povysil, Gundula, additional, Dhindsa, Ryan S., additional, Stanley, Kate E., additional, Allen, Andrew S., additional, Feng, Yen-Chen Anne, additional, Howrigan, Daniel P., additional, Abbott, Liam E., additional, Tashman, Katherine, additional, Cerrato, Felecia, additional, Cusick, Caroline, additional, Singh, Tarjinder, additional, Heyne, Henrike, additional, Byrnes, Andrea E., additional, Churchhouse, Claire, additional, Watts, Nick, additional, Solomonson, Matthew, additional, Lal, Dennis, additional, Gupta, Namrata, additional, Neale, Benjamin M., additional, Cavalleri, Gianpiero L., additional, Cossette, Patrick, additional, Cotsapas, Chris, additional, De Jonghe, Peter, additional, Dixon-Salazar, Tracy, additional, Guerrini, Renzo, additional, Hakonarson, Hakon, additional, Heinzen, Erin L., additional, Helbig, Ingo, additional, Kwan, Patrick, additional, Marson, Anthony G., additional, Petrovski, Slavé, additional, Kamalakaran, Sitharthan, additional, Sisodiya, Sanjay M., additional, Stewart, Randy, additional, Weckhuysen, Sarah, additional, Depondt, Chantal, additional, Dlugos, Dennis J., additional, Scheffer, Ingrid E., additional, Striano, Pasquale, additional, Freyer, Catharine, additional, Krause, Roland, additional, May, Patrick, additional, McKenna, Kevin, additional, Regan, Brigid M., additional, Bennett, Caitlin A., additional, Leu, Costin, additional, Leech, Stephanie L., additional, O’Brien, Terence J., additional, Todaro, Marian, additional, Stamberger, Hannah, additional, Andrade, Danielle M., additional, Ali, Quratulain Zulfiqar, additional, Sadoway, Tara R., additional, Krestel, Heinz, additional, Schaller, André, additional, Papacostas, Savvas S., additional, Kousiappa, Ioanna, additional, Tanteles, George A., additional, Christou, Yiolanda, additional, Štěrbová, Katalin, additional, Vlčková, Markéta, additional, Sedláčková, Lucie, additional, Laššuthová, Petra, additional, Klein, Karl Martin, additional, Rosenow, Felix, additional, Reif, Philipp S., additional, Knake, Susanne, additional, Neubauer, Bernd A., additional, Zimprich, Friedrich, additional, Feucht, Martha, additional, Reinthaler, Eva M., additional, Kunz, Wolfram S., additional, Zsurka, Gábor, additional, Surges, Rainer, additional, Baumgartner, Tobias, additional, von Wrede, Randi, additional, Pendziwiat, Manuela, additional, Muhle, Hiltrud, additional, Rademacher, Annika, additional, van Baalen, Andreas, additional, von Spiczak, Sarah, additional, Stephani, Ulrich, additional, Afawi, Zaid, additional, Korczyn, Amos D., additional, Kanaan, Moien, additional, Canavati, Christina, additional, Kurlemann, Gerhard, additional, Müller-Schlüter, Karen, additional, Kluger, Gerhard, additional, Häusler, Martin, additional, Blatt, Ilan, additional, Lemke, Johannes R., additional, Krey, Ilona, additional, Weber, Yvonne G., additional, Wolking, Stefan, additional, Becker, Felicitas, additional, Lauxmann, Stephan, additional, Boßelmann, Christian, additional, Kegele, Josua, additional, Hengsbach, Christian, additional, Rau, Sarah, additional, Steinhoff, Bernhard J., additional, Schulze-Bonhage, Andreas, additional, Borggräfe, Ingo, additional, Schankin, Christoph J., additional, Schubert-Bast, Susanne, additional, Schreiber, Herbert, additional, Mayer, Thomas, additional, Korinthenberg, Rudolf, additional, Brockmann, Knut, additional, Wolff, Markus, additional, Dennig, Dieter, additional, Madeleyn, Rene, additional, Kälviäinen, Reetta, additional, Saarela, Anni, additional, Timonen, Oskari, additional, Linnankivi, Tarja, additional, Lehesjoki, Anna-Elina, additional, Rheims, Sylvain, additional, Lesca, Gaetan, additional, Ryvlin, Philippe, additional, Maillard, Louis, additional, Valton, Luc, additional, Derambure, Philippe, additional, Bartolomei, Fabrice, additional, Hirsch, Edouard, additional, Michel, Véronique, additional, Chassoux, Francine, additional, Rees, Mark I., additional, Chung, Seo-Kyung, additional, Pickrell, William O., additional, Powell, Robert, additional, Baker, Mark D., additional, Fonferko-Shadrach, Beata, additional, Lawthom, Charlotte, additional, Anderson, Joseph, additional, Schneider, Natascha, additional, Balestrini, Simona, additional, Zagaglia, Sara, additional, Braatz, Vera, additional, Johnson, Michael R., additional, Auce, Pauls, additional, Sills, Graeme J., additional, Baum, Larry W., additional, Sham, Pak C., additional, Cherny, Stacey S., additional, Lui, Colin H.T., additional, Delanty, Norman, additional, Doherty, Colin P., additional, Shukralla, Arif, additional, El-Naggar, Hany, additional, Widdess-Walsh, Peter, additional, Barišić, Nina, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Castellotti, Barbara, additional, Granata, Tiziana, additional, Ragona, Francesca, additional, Zara, Federico, additional, Iacomino, Michele, additional, Riva, Antonella, additional, Madia, Francesca, additional, Vari, Maria Stella, additional, Salpietro, Vincenzo, additional, Scala, Marcello, additional, Mancardi, Maria Margherita, additional, Nobili, Lino, additional, Amadori, Elisabetta, additional, Giacomini, Thea, additional, Bisulli, Francesca, additional, Pippucci, Tommaso, additional, Licchetta, Laura, additional, Minardi, Raffaella, additional, Tinuper, Paolo, additional, Muccioli, Lorenzo, additional, Mostacci, Barbara, additional, Gambardella, Antonio, additional, Labate, Angelo, additional, Annesi, Grazia, additional, Manna, Lorella, additional, Gagliardi, Monica, additional, Parrini, Elena, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Bianchini, Claudia, additional, Montomoli, Martino, additional, Doccini, Viola, additional, Barba, Carmen, additional, Hirose, Shinichi, additional, Ishii, Atsushi, additional, Suzuki, Toshimitsu, additional, Inoue, Yushi, additional, Yamakawa, Kazuhiro, additional, Beydoun, Ahmad, additional, Nasreddine, Wassim, additional, Khoueiry Zgheib, Nathalie, additional, Tumiene, Birute, additional, Utkus, Algirdas, additional, Sadleir, Lynette G., additional, King, Chontelle, additional, Caglayan, S. Hande, additional, Arslan, Mutluay, additional, Yapıcı, Zuhal, additional, Topaloglu, Pınar, additional, Kara, Bulent, additional, Yis, Uluc, additional, Turkdogan, Dilsad, additional, Gundogdu-Eken, Aslı, additional, Bebek, Nerses, additional, Uğur-İşeri, Sibel, additional, Baykan, Betül, additional, Salman, Barış, additional, Haryanyan, Garen, additional, Yücesan, Emrah, additional, Kesim, Yeşim, additional, Özkara, Çiğdem, additional, Tsai, Meng-Han, additional, Ho, Chen-Jui, additional, Lin, Chih-Hsiang, additional, Lin, Kuang-Lin, additional, Chou, I-Jun, additional, Poduri, Annapurna, additional, Shiedley, Beth R., additional, Shain, Catherine, additional, Noebels, Jeffrey L., additional, Goldman, Alicia, additional, Busch, Robyn M., additional, Jehi, Lara, additional, Najm, Imad M., additional, Ferguson, Lisa, additional, Khoury, Jean, additional, Glauser, Tracy A., additional, Clark, Peggy O., additional, Buono, Russell J., additional, Ferraro, Thomas N., additional, Sperling, Michael R., additional, Lo, Warren, additional, Privitera, Michael, additional, French, Jacqueline A., additional, Schachter, Steven, additional, Kuzniecky, Ruben I., additional, Devinsky, Orrin, additional, Hegde, Manu, additional, Greenberg, David A., additional, Ellis, Colin A., additional, Goldberg, Ethan, additional, Helbig, Katherine L., additional, Cosico, Mahgenn, additional, Vaidiswaran, Priya, additional, Fitch, Eryn, additional, Berkovic, Samuel F., additional, Lerche, Holger, additional, Lowenstein, Daniel H., additional, and Goldstein, David B., additional

Published
2021
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40. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author

Koko, Mahmoud, primary, Krause, Roland, additional, Sander, Thomas, additional, Bobbili, Dheeraj Reddy, additional, Nothnagel, Michael, additional, May, Patrick, additional, Lerche, Holger, additional, Feng, Yen-Chen Anne, additional, Howrigan, Daniel P, additional, Abbott, Liam E, additional, Tashman, Katherine, additional, Cerrato, Felecia, additional, Singh, Tarjinder, additional, Heyne, Henrike, additional, Byrnes, Andrea, additional, Churchhouse, Claire, additional, Watts, Nick, additional, Solomonson, Matthew, additional, Lal, Dennis, additional, Heinzen, Erin L, additional, Dhindsa, Ryan S, additional, Stanley, Kate E, additional, Cavalleri, Gianpiero L, additional, Hakonarson, Hakon, additional, Helbig, Ingo, additional, Weckhuysen, Sarah, additional, Petrovski, Slavé, additional, Kamalakaran, Sitharthan, additional, Sisodiya, Sanjay M, additional, Cossette, Patrick, additional, Cotsapas, Chris, additional, DeJonghe, Peter, additional, Dixon-Salazar, Tracy, additional, Guerrini, Renzo, additional, Kwan, Patrick, additional, Marson, Anthony G, additional, Stewart, Randy, additional, Depondt, Chantal, additional, Dlugos, Dennis J, additional, Scheffer, Ingrid E, additional, Striano, Pasquale, additional, Freyer, Catharine, additional, McKenna, Kevin, additional, Regan, Brigid M, additional, Bellows, Susannah T, additional, Leu, Costin, additional, Bennett, Caitlin A, additional, Johns, Esther M C, additional, Macdonald, Alexandra, additional, Shilling, Hannah, additional, Burgess, Rosemary, additional, Weckhuysen, Dorien, additional, Bahlo, Melanie, additional, O'Brien, Terence J, additional, Todaro, Marian, additional, Stamberger, Hannah, additional, Andrade, Danielle M, additional, Sadoway, Tara R, additional, Mo, Kelly, additional, Krestel, Heinz, additional, Gallati, Sabina, additional, Papacostas, Savvas S, additional, Kousiappa, Ioanna, additional, Tanteles, George A, additional, Štěrbová, Katalin, additional, Vlčková, Markéta, additional, Sedláčková, Lucie, additional, Laššuthová, Petra, additional, Klein, Karl Martin, additional, Rosenow, Felix, additional, Reif, Philipp S, additional, Knake, Susanne, additional, Kunz, Wolfram S, additional, Zsurka, Gábor, additional, Elger, Christian E, additional, Bauer, Jürgen, additional, Rademacher, Michael, additional, Pendziwiat, Manuela, additional, Muhle, Hiltrud, additional, Rademacher, Annika, additional, vanBaalen, Andreas, additional, vonSpiczak, Sarah, additional, Stephani, Ulrich, additional, Afawi, Zaid, additional, Korczyn, Amos D, additional, Kanaan, Moien, additional, Canavati, Christina, additional, Kurlemann, Gerhard, additional, Müller-Schlüter, Karen, additional, Kluger, Gerhard, additional, Häusler, Martin, additional, Blatt, Ilan, additional, Lemke, Johannes R, additional, Krey, Ilona, additional, Weber, Yvonne G, additional, Wolking, Stefan, additional, Becker, Felicitas, additional, Hengsbach, Christian, additional, Rau, Sarah, additional, Maisch, Ana F, additional, Steinhoff, Bernhard J, additional, Schulze-Bonhage, Andreas, additional, Schubert-Bast, Susanne, additional, Schreiber, Herbert, additional, Borggräfe, Ingo, additional, Schankin, Christoph J, additional, Mayer, Thomas, additional, Korinthenberg, Rudolf, additional, Brockmann, Knut, additional, Dennig, Dieter, additional, Madeleyn, Rene, additional, Kälviäinen, Reetta, additional, Auvinen, Pia, additional, Saarela, Anni, additional, Linnankivi, Tarja, additional, Lehesjoki, Anna-Elina, additional, Rees, Mark I, additional, Chung, Seo-Kyung, additional, Pickrell, William O, additional, Powell, Robert, additional, Schneider, Natascha, additional, Balestrini, Simona, additional, Zagaglia, Sara, additional, Braatz, Vera, additional, Johnson, Michael R, additional, Auce, Pauls, additional, Sills, Graeme J, additional, Baum, Larry W, additional, Sham, Pak C, additional, Cherny, Stacey S, additional, Lui, Colin H T, additional, Barišić, Nina, additional, Delanty, Norman, additional, Doherty, Colin P, additional, Shukralla, Arif, additional, McCormack, Mark, additional, El-Naggar, Hany, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Castellotti, Barbara, additional, Granata, Tiziana, additional, Zara, Federico, additional, Iacomino, Michele, additional, Madia, Francesca, additional, Vari, Maria Stella, additional, Mancardi, Maria Margherita, additional, Salpietro, Vincenzo, additional, Bisulli, Francesca, additional, Tinuper, Paolo, additional, Licchetta, Laura, additional, Pippucci, Tommaso, additional, Stipa, Carlotta, additional, Minardi, Raffaella, additional, Gambardella, Antonio, additional, Labate, Angelo, additional, Annesi, Grazia, additional, Manna, Lorella, additional, Gagliardi, Monica, additional, Parrini, Elena, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Bianchini, Claudia, additional, Montomoli, Martino, additional, Doccini, Viola, additional, Marini, Carla, additional, Suzuki, Toshimitsu, additional, Inoue, Yushi, additional, Yamakawa, Kazuhiro, additional, Tumiene, Birute, additional, Sadleir, Lynette G, additional, King, Chontelle, additional, Mountier, Emily, additional, Caglayan, Hande S, additional, Arslan, Mutluay, additional, Yapıcı, Zuhal, additional, Yis, Uluc, additional, Topaloglu, Pınar, additional, Kara, Bulent, additional, Turkdogan, Dilsad, additional, Gundogdu-Eken, Aslı, additional, Bebek, Nerses, additional, Uğur-İşeri, Sibel, additional, Baykan, Betül, additional, Salman, Barış, additional, Haryanyan, Garen, additional, Yücesan, Emrah, additional, Kesim, Yeşim, additional, Özkara, Çiğdem, additional, Poduri, Annapurna, additional, Shiedley, Beth R, additional, Shain, Catherine, additional, Buono, Russell J, additional, Ferraro, Thomas N, additional, Sperling, Michael R, additional, Lo, Warren, additional, Privitera, Michael, additional, French, Jacqueline A, additional, Schachter, Steven, additional, Kuzniecky, Ruben I, additional, Devinsky, Orrin, additional, Hegde, Manu, additional, Khankhanian, Pouya, additional, Helbig, Katherine L, additional, Ellis, Colin A, additional, Spalletta, Gianfranco, additional, Piras, Fabrizio, additional, Piras, Federica, additional, Gili, Tommaso, additional, Ciullo, Valentina, additional, Reif, Andreas, additional, McQuillin, Andrew, additional, Bass, Nick, additional, McIntosh, Andrew, additional, Blackwood, Douglas, additional, Johnstone, Mandy, additional, Palotie, Aarno, additional, Pato, Michele T, additional, Pato, Carlos N, additional, Bromet, Evelyn J, additional, Carvalho, Celia Barreto, additional, Achtyes, Eric D, additional, Azevedo, Maria Helena, additional, Kotov, Roman, additional, Lehrer, Douglas S, additional, Malaspina, Dolores, additional, Marder, Stephen R, additional, Medeiros, Helena, additional, Morley, Christopher P, additional, Perkins, Diana O, additional, Sobell, Janet L, additional, Buckley, Peter F, additional, Macciardi, Fabio, additional, Rapaport, Mark H, additional, Knowles, James A, additional, Cohort, Genomic Psychiatry, additional, Fanous, Ayman H, additional, McCarroll, Steven A, additional, Gupta, Namrata, additional, Gabriel, Stacey B, additional, Daly, Mark J, additional, Lander, Eric S, additional, Lowenstein, Daniel H, additional, Goldstein, David B, additional, Berkovic, Samuel F, additional, and Neale, Benjamin M, additional

Published
2021
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41. Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Author

Wolking, Stefan, Campbell, Ciarán, Stapleton, Caragh, McCormack, Mark, Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Cavalleri, Gianpiero L., Lerche, Holger, and Epipgx Consortium

Subjects
Neurologie [D14] [Sciences de la santé humaine], Neurology [D14] [Human health sciences], respiratory system, musculoskeletal system, respiratory tract diseases
Abstract

Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.

Published
2021

42. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author

Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., Cossette, Patrick, Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Consortium, Epipgx, Berkovic, Samuel, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Petrovski, Slave, Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Sisodiya, Sanjay M., Girard, Simon L., and Cossette, Patrick

Abstract

Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.

Published
2021

43. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.

Abstract

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

44. Multi-Source Data ETL (Extract, Transform, Load) for a Genetic Epilepsy Diagnosis and Treatment Dashboard.

Author

PÉREZ GARRIGA, Ariadna, HONRATH, Philipp, WOLKING, Stefan, COLDEWEY, Beatrice, BOZKIR, Susann A., MAY, Patrick, WEBER, Yvonne, RÖHRIG, Rainer, and LIPPRANDT, Myriam

Abstract

The growing number of genes identified in relation to epilepsy represents a major breakthrough in diagnosis and treatment, but experts face the challenge of efficiently accessing and consolidating the vast amount of genetic data available. Therefore, we present the process of transforming data from different sources and formats into an Entity-Attribute-Value (EAV) model database. Combined with the use of standard coding systems, this approach will provide a scalable and adaptable database to present the data in a comprehensive way to experts via a dashboard. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Epilepsy Subtype-Specific Copy Number Burden Observed in a Genome-Wide Study of 17 458 Subjects

Author

Niestroj, Lisa-Marie, Perez-Palma, Eduardo, Howrigan, Daniel P., Zhou, Yadi, Cheng, Feixiong, Saarentaus, Elmo, Nürnberg, Peter, Stevelink, Remi, Daly, Mark J., Palotie, Aarno, Lal, Dennis, Feng, Yen-Chen Anne, Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Churchhouse, Claire, Gupta, Namrata, Neale, Benjamin M., Berkovic, Samuel F., Lerche, Holger, Goldstein, David B., Lowenstein, Daniel H., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Weckhuysen, Sarah, Stamberger, Hannah, De Jonghe, Peter, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Muccioli, Lorenzo, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Mameniskiene, Ruta, Utkus, Algirdas, Praninskiene, Ruta, Grikiniene, Jurgita, Samaitiene, Ruta, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yesim, Özkara, Çigdem, Sheidley, Beth R., Shain, Catherine, Poduri, Annapurna, Buono, Russell J, Ferraro, Thomas N, Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, YÜCESAN, EMRAH, Niestroj L.-M., Perez-Palma E., Howrigan D.P., Zhou Y., Cheng F., Saarentaus E., Nurnberg P., Stevelink R., Daly M.J., Palotie A., Lal D, Epi 25 Collaborative, Bisulli F., Tinuper P., Licchetta L., and Epi25 Collaborative

Subjects
Developmental and epileptic encephalopathy, Male, 0301 basic medicine, DNA Copy Number Variations, Disease, Bioinformatics, Genome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, copy number variation, developmental and epileptic encephalopathy, epilepsy, focal epilepsy, genetic generalized epilepsy, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Generalized epilepsy, DNA Copy Number Variation, Copy number variation, business.industry, Breakpoint, Focal epilepsy, Original Articles, medicine.disease, 3. Good health, Genetic generalized epilepsy, 030104 developmental biology, Female, Human medicine, Neurology (clinical), Personalized medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
Abstract

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

Published
2020
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46. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author

Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, Lerche, Holger, Wolking, Stefan, Schulz, Herbert, Nies, Anne T., McCormack, Mark, Schaeffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl M., Krenn, Martin, Moller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay, Schwab, Matthias, Sander, Thomas, and Lerche, Holger

Abstract

Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10(-5)) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

Published
2020

47. Testing association of rare genetic variants with resistance to three common antiseizure medications

Author

European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, EpiPGX Consortium, European Commission - EC [sponsor], Wolking, Stefan, Moreau, Claudia, Nies, Anne T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weber, Yvonne G., Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay M., Cossette, Patrick, Girard, Simon L., Lerche, Holger, and EpiPGX Consortium

Abstract

Objective Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set–based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

Published
2020

48. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

Author

EpiPGx Consortium, Wolking, Stefan, Schulz, Herbert, Nies, Anne T, McCormack, Mark, Schäffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl Martin, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico J., Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay M., Schwab, Matthias, Sander, Thomas, Lerche, Holger, EpiPGx Consortium, Wolking, Stefan, Schulz, Herbert, Nies, Anne T, McCormack, Mark, Schäffeler, Elke, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Klein, Karl Martin, Krenn, Martin, Møller, Rikke S., Nikanorova, Marina, Weckhuysen, Sarah, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico J., Zimprich, Fritz, Weber, Yvonne G., Krause, Roland, Sisodiya, Sanjay M., Schwab, Matthias, Sander, Thomas, and Lerche, Holger

Abstract

Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

Published
2020

49. Testing association of rare genetic variants with resistance to three common antiseizure medications

Author

Wolking, Stefan, Moreau, Claudia, Nies, Anne A.T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke Steensbjerre, Nikanorova, Marina, Weber, Yvonne Y.G., Weckhuysen, Sarah, Cavalleri, Gianpiero, Delanty, Norman, Depondt, Chantal, Johnson, Michael, Koeleman, B.P.C., Kunz, Wolfram W.S., Marson, Anthony Guy, Sander, Ley J.W., Sills, Graeme, Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay, Cossette, Patrick, Girard, Simon S.L., Lerche, Holger, Wolking, Stefan, Moreau, Claudia, Nies, Anne A.T., Schaeffeler, Elke, McCormack, Mark, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Krenn, Martin, Møller, Rikke Steensbjerre, Nikanorova, Marina, Weber, Yvonne Y.G., Weckhuysen, Sarah, Cavalleri, Gianpiero, Delanty, Norman, Depondt, Chantal, Johnson, Michael, Koeleman, B.P.C., Kunz, Wolfram W.S., Marson, Anthony Guy, Sander, Ley J.W., Sills, Graeme, Striano, Pasquale, Zara, Federico, Zimprich, Fritz, Schwab, Matthias, Krause, Roland, Sisodiya, Sanjay, Cossette, Patrick, Girard, Simon S.L., and Lerche, Holger

Abstract

Objective: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set–based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2020

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