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1. Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations

Author

Stevelink, Remi, Luykx, Jurjen J, Lin, Bochao D, Leu, Costin, Lal, Dennis, Smith, Alexander W, Schijven, Dick, Carpay, Johannes A, Rademaker, Koen, Baldez, Roiza A Rodrigues, Devinsky, Orrin, Braun, Kees PJ, Jansen, Floor E, Smit, Dirk JA, Koeleman, Bobby PC, Abou‐Khalil, Bassel, Auce, Pauls, Avbersek, Andreja, Bahlo, Melanie, Balding, David J, Bast, Thomas, Baum, Larry, Becker, Albert J, Becker, Felicitas, Berghuis, Bianca, Berkovic, Samuel F, Boysen, Katja E, Bradfield, Jonathan P, Brody, Lawrence C, Buono, Russell J, Campbell, Ellen, Cascino, Gregory D, Catarino, Claudia B, Cavalleri, Gianpiero L, Cherny, Stacey S, Chinthapalli, Krishna, Coffey, Alison J, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, Craig, John J, de Haan, Gerrit‐Jan, De Jonghe, Peter, de Kovel, Carolien GF, Delanty, Norman, Depondt, Chantal, Dlugos, Dennis J, Doherty, Colin P, Elger, Christian E, Eriksson, Johan G, Ferraro, Thomas N, Feucht, Martha, Francis, Ben, Franke, Andre, French, Jacqueline A, Freytag, Saskia, Gaus, Verena, Geller, Eric B, Gieger, Christian, Glauser, Tracy, Glynn, Simon, Goldstein, David B, Gui, Hongsheng, Guo, Youling, Haas, Kevin F, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, Heinzen, Erin L, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, Andrés, Jamnadas‐Khoda, Jennifer, Johnson, Michael R, Kälviäinen, Reetta, Kantanen, Anne‐Mari, Kasperavičiūte, Dalia, Trenite, Dorothee Kasteleijn‐Nolst, Kirsch, Heidi E, Knowlton, Robert C, Krause, Roland, Krenn, Martin, Kunz, Wolfram S, Kuzniecky, Ruben, Kwan, Patrick, Lau, Yu‐Lung, Lehesjoki, Anna‐Elina, Lerche, Holger, Lieb, Wolfgang, Lindhout, Dick, Lo, Warren D, Lopes‐Cendes, Iscia, Lowenstein, Daniel H, Malovini, Alberto, Marson, Anthony G, Mayer, Thomas, McCormack, Mark, and Mills, James L

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Genetics, Brain Disorders, Clinical Research, Human Genome, Neurodegenerative, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Algorithms, Beta Rhythm, Cohort Studies, Databases, Factual, Electroencephalography, Epilepsy, Generalized, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Mendelian Randomization Analysis, Risk Assessment, Theta Rhythm, beta power, EEG, generalized epilepsy, GGE, oscillations, PRS, International League Against Epilepsy Consortium on Complex Epilepsies, Epi25 Collaborative, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

Published
2021

2. Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies

Author

Abou‐Khalil, Bassel, Afawi, Zaid, Allen, Andrew S, Bautista, Jocelyn F, Bellows, Susannah T, Berkovic, Samuel F, Bluvstein, Judith, Burgess, Rosemary, Cascino, Gregory, Cossette, Patrick, Cristofaro, Sabrina, Crompton, Douglas E, Delanty, Norman, Devinsky, Orrin, Dlugos, Dennis, Ellis, Colin A, Epstein, Michael P, Fountain, Nathan B, Freyer, Catharine, Geller, Eric B, Glauser, Tracy, Glynn, Simon, Goldberg‐Stern, Hadassa, Goldstein, David B, Gravel, Micheline, Haas, Kevin, Haut, Sheryl, Heinzen, Erin L, Kirsch, Heidi E, Kivity, Sara, Knowlton, Robert, Korczyn, Amos D, Kossoff, Eric, Kuzniecky, Ruben, Loeb, Rebecca, Lowenstein, Daniel H, Marson, Anthony G, McCormack, Mark, McKenna, Kevin, Mefford, Heather C, Motika, Paul, Mullen, Saul A, J. O'Brien, Terence, Ottman, Ruth, Paolicchi, Juliann, Parent, Jack M, Paterson, Sarah, Petrou, Steven, Petrovski, Slavé, Owen Pickrell, William, Poduri, Annapurna, Rees, Mark I, Sadleir, Lynette G, Scheffer, Ingrid E, Shih, Jerry, Singh, Rani, Sirven, Joseph, Smith, Michael, Smith, Phil EM, Thio, Liu Lin, Thomas, Rhys H, Venkat, Anu, Vining, Eileen, Von Allmen, Gretchen, Weisenberg, Judith, Widdess‐Walsh, Peter, and Winawer, Melodie R

Subjects
Neurodegenerative, Neurosciences, Epilepsy, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Electroencephalography, Epileptic Syndromes, Female, Humans, Latent Class Analysis, Male, Pedigree, Phenotype, epilepsy, genetics, latent class analysis, phenotype, Epi4K Consortium, Clinical Sciences, Neurology & Neurosurgery
Abstract

ObjectiveClassification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks.MethodsWe used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes.ResultsA total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types.SignificanceQuantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.

Published
2019

3. A randomized controlled trial of levodopa in patients with Angelman syndrome

Author

Tan, Wen‐Hann, Bird, Lynne M, Sadhwani, Anjali, Barbieri‐Welge, Rene L, Skinner, Steven A, Horowitz, Lucia T, Bacino, Carlos A, Noll, Lisa M, Fu, Cary, Hundley, Rachel J, Wink, Logan K, Erickson, Craig A, Barnes, Gregory N, Slavotinek, Anne, Jeremy, Rita, Rotenberg, Alexander, Kothare, Sanjeev V, Olson, Heather E, Poduri, Annapurna, Nespeca, Mark P, Chu, Hillary C, Willen, Jennifer M, Haas, Kevin F, Weeber, Edwin J, and Rufo, Paul A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Clinical Research, Brain Disorders, Prevention, Pediatric, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Angelman Syndrome, Animals, Biomarkers, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Disease Models, Animal, Humans, Levodopa, Long-Term Potentiation, Mice, Neuropsychological Tests, Treatment Outcome, calcium-calmodulin-dependent protein kinase type 2, clinical trial, developmental disabilities, inborn genetic diseases, rare disease, UBE3A, Genetics, Clinical sciences
Abstract

Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin-dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.

Published
2018

4. Phenotypic analysis of 303 multiplex families with common epilepsies.

Author

Abou-Khalil, Bassel, Afawi, Zaid, Allen, Andrew S, Bautista, Jocelyn F, Bellows, Susannah T, Berkovic, Samuel F, Bluvstein, Judith, Burgess, Rosemary, Cascino, Gregory, Cops, Elisa J, Cossette, Patrick, Cristofaro, Sabrina, Crompton, Douglas E, Delanty, Norman, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P, Fountain, Nathan B, Freyer, Catharine, Garry, Sarah I, Geller, Eric B, Glauser, Tracy, Glynn, Simon, Goldberg-Stern, Hadassa, Goldstein, David B, Gravel, Micheline, Haas, Kevin, Haut, Sheryl, Heinzen, Erin L, Kirsch, Heidi E, Kivity, Sara, Knowlton, Robert, Korczyn, Amos D, Kossoff, Eric, Kuzniecky, Ruben, Loeb, Rebecca, Lowenstein, Daniel H, Marson, Anthony G, McCormack, Mark, McKenna, Kevin, Mefford, Heather C, Motika, Paul, Mullen, Saul A, O'Brien, Terence J, Ottman, Ruth, Paolicchi, Juliann, Parent, Jack M, Paterson, Sarah, Petrovski, Slave, Pickrell, William Owen, Poduri, Annapurna, Rees, Mark I, Sadleir, Lynette G, Scheffer, Ingrid E, Shih, Jerry, Singh, Rani, Sirven, Joseph, Smith, Michael, Smith, Phil EM, Thio, Liu Lin, Thomas, Rhys H, Venkat, Anu, Vining, Eileen, Von Allmen, Gretchen, Weisenberg, Judith, Widdess-Walsh, Peter, and Winawer, Melodie R

Subjects
Genetics, Clinical Research, Brain Disorders, Pediatric, Neurosciences, Epilepsy, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Age of Onset, Child, Child, Preschool, Epilepsy, Generalized, Family Health, Female, Humans, Male, Pedigree, Phenotype, Sex Factors, Young Adult, epilepsy, multiplex families, phenotype, genetics, Epi4K Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.

Published
2017

5. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Author

Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stéphanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Dimova, Petia, Djémié, Tania, Gormley, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Johanna, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Kuhlenbäumer, Gregor, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R, Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Møller, Rikke S, Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Pendziwiat, Manuela, Robbiano, Angela, Roelens, Filip, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M, Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, von Spiczak, Sarah, Weber, Yvonne, Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K, Andermann, Eva, Andermann, Frederick, Amron, Dina, Bautista, Jocelyn F, Berkovic, Samuel F, Bluvstein, Judith, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P, Fiol, Miguel, Fountain, Nathan B, French, Jacqueline, Friedman, Daniel, Geller, Eric B, Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl R, Hayward, Jean, Helmers, Sandra L, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E, Knowlton, Robert C, Kossoff, Eric H, Kuperman, Rachel, Kuzniecky, Ruben, Lowenstein, Daniel H, McGuire, Shannon M, Motika, Paul V, Novotny, Edward J, Ottman, Ruth, Paolicchi, Juliann M, Parent, Jack, Park, Kristen, Poduri, Annapurna, Sadleir, Lynette, Scheffer, Ingrid E, Shellhaas, Renée A, Sherr, Elliott, Shih, Jerry J, Singh, Rani, Sirven, Joseph, Smith, Michael C, Sullivan, Joe, and Thio, Liu Lin

Subjects
Genetics, Pediatric, Neurosciences, Epilepsy, Brain Disorders, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Cohort Studies, Dynamin I, Exome, Fatty Acid Synthase, Type I, Female, Gene Regulatory Networks, Humans, Infant, Newborn, Lennox Gastaut Syndrome, Male, Mutation, Protein Interaction Maps, Receptors, GABA-B, Ryanodine Receptor Calcium Release Channel, Spasms, Infantile, Synaptic Transmission, EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Published
2014

6. The epilepsy phenome/genome project.

Author

EPGP Collaborative, Abou-Khalil, Bassel, Alldredge, Brian, Bautista, Jocelyn, Berkovic, Sam, Bluvstein, Judith, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Cristofaro, Sabrina, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael, Fahlstrom, Robyn, Fiol, Miguel, Fountain, Nathan, Fox, Kristen, French, Jacqueline, Freyer Karn, Catharine, Friedman, Daniel, Geller, Eric, Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl, Hayward, Jean, Helmers, Sandra, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi, Knowlton, Robert, Kossoff, Eric, Kuperman, Rachel, Kuzniecky, Ruben, Lowenstein, Daniel, McGuire, Shannon, Motika, Paul, Nesbitt, Gerard, Novotny, Edward, Ottman, Ruth, Paolicchi, Juliann, Parent, Jack, Park, Kristen, Poduri, Annapurna, Risch, Neil, Sadleir, Lynette, Scheffer, Ingrid, Shellhaas, Renee, Sherr, Elliott, Shih, Jerry J, Shinnar, Shlomo, Singh, Rani, Sirven, Joseph, Smith, Michael, Sullivan, Joe, Thio, Liu Lin, Venkat, Anu, Vining, Eileen, von Allmen, Gretchen, Weisenberg, Judith, Widdess-Walsh, Peter, and Winawer, Melodie

Subjects
EPGP Collaborative, Humans, Epilepsy, Oligonucleotide Array Sequence Analysis, Retrospective Studies, Genetic Research, Genotype, Phenotype, Research Design, Information Management, Clinical Research, Neurodegenerative, Neurosciences, Brain Disorders, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Statistics, Clinical Sciences, Statistics & Probability
Abstract

BackgroundEpilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy.ResultsEPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants.ConclusionsEPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

Published
2013

7. Erratum : De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies (American Journal of Human Genetics (2014) 95(4) (360–370)(S0002929714003838)(10.1016/j.ajhg.2014.08.013))

Author

Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stéphanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Dimova, Petia, Djémié, Tania, Gormley, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Johanna A., Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Kuhlenbäumer, Gregor, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R., Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Møller, Rikke S., Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Pendziwiat, Manuela, Robbiano, Angela, Roelens, Filip, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M., Sisodiya, Sanjay M., Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, von Spiczak, Sarah, Weber, Yvonne G., Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K., Andermann, Eva, Andermann, Frederick, Amrom, Dina, Bautista, Jocelyn F., Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Fiol, Miguel, Fountain, Nathan B., French, Jacqueline, Friedman, Daniel, Geller, Eric B., Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl R., Hayward, Jean, Helmers, Sandra L., Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Knowlton, Robert C., Kossoff, Eric H., Kuperman, Rachel, Kuzniecky, Ruben, Lowenstein, Daniel H., McGuire, Shannon M., Motika, Paul V., Novotny, Edward J., Ottman, Ruth, Paolicchi, Juliann M., Parent, Jack, Park, Kristen, Poduri, Annapurna, Sadleir, Lynette G., Scheffer, Ingrid E., Shellhaas, Renée A, Sherr, Elliott, Shih, Jerry J., Singh, Rani, Sirven, Joseph, Smith, Michael C., Sullivan, Joe, Thio, Liu Lin, Venkat, Anu, Vining, Eileen P. G., Von Allmen, Gretchen K., Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Allen, Andrew S., Cossette, Patrick, Delanty, Norman, Eichler, Evan E., Goldstein, David B., Han, Yujun, Heinzen, Erin L., Johnson, Michael R., Marson, Anthony G., Mefford, Heather C., Nieh, Sahar Esmaeeli, O'Brien, Terence J., Petrou, Stephen, Petrovski, Slavé, and Ruzzo, Elizabeth K.

Subjects
Genetics, Genetics(clinical)
Abstract

(The American Journal of Human Genetics 95, 360–370; October 2, 2014) In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom's name was misspelled as Amron. The authors regret the error.

Published
2017

8. Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

Author

Allen, Andrew S, Berkovic, Samuel F, Bridgers, Joshua, Cossette, Patrick, Dlugos, Dennis, Epstein, Michael P, Glauser, Tracy, Goldstein, David B, Heinzen, Erin L, Jiang, Yu, Johnson, Michael R, Kuzniecky, Ruben, Lowenstein, Daniel H, Marson, Anthony G, Mefford, Heather C, O'Brien, Terence J, Ottman, Ruth, Petrou, Steven, Petrovski, Slave, Poduri, Annapurna, Ren, Zhong, Scheffer, Ingrid E, Sherr, Elliott, Wang, Quanli, Balling, Rudi, Barisic, Nina, Baulac, Stephanie, Caglayan, Hande, Craiu, Dana, De Jonghe, Peter, Depienne, Christel, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jaehn, Johanna, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R, Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Moller, Rikke S, Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M, Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, von Spiczak, Sarah, Weber, Yvonne, Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K, Amrom, Dina, Andermann, Eva, Andermann, Frederick, Bautista, Jocelyn F, Bluvstein, Judith, Cascino, Gregory D, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Fiol, Miguel E, Fountain, Nathan B, French, Jacqueline, Friedman, Daniel, Haas, Kevin, Haut, Sheryl R, Hayward, Jean, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E, Kossoff, Eric H, Kuperman, Rachel, McGuire, Shannon M, Motika, Paul V, Novotny, Edward J, Paolicchi, Juliann M, Parent, Jack, Park, Kristen, Shellhaas, Renee A, Sirven, Joseph, Smith, Michael C, Sullivan, Joseph, Thio, Liu Lin, Venkat, Anu, Vining, Eileen PG, Von Allmen, Gretchen K, Weisenberg, Judith L, Widdess-Walsh, Peter, Winawer, Melodie R, Consortium, Epi4K, Consortium, EuroEPINOMICS-RES, Project, Epilepsy Phenome Genome, Epi4K Consortium, EuroEPINOMICS- RES Consortium, and Epilepsy Phenome Genome Project

Subjects
0301 basic medicine, Linkage disequilibrium, medicine.medical_specialty, genetic structures, Population, Disequilibrium, Short Report, Genome-wide association study, Biology, Bioinformatics, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Epilepsy Phenome/Genome Project, medicine, Genetics, Journal Article, Humans, Genetics(clinical), Genetic Predisposition to Disease, education, Genetics (clinical), education.field_of_study, Polymorphism, Genetic, Lennox Gastaut Syndrome, Infant, Transmission disequilibrium test, medicine.disease, Multicenter Study, Chemistry, 030104 developmental biology, Medical genetics, Human medicine, medicine.symptom, Spasms, Infantile, 030217 neurology & neurosurgery, Lennox–Gastaut syndrome, Genome-Wide Association Study
Abstract

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population.

Published
2017

9. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

Koko, M., Motelow, J. E., Stanley, K. E., Bobbili, D. R., Dhindsa, R. S., May, P., Alldredge, B. K., Allen, A. S., Altmuller, J., Amrom, D., Andermann, E., Auce, P., Avbersek, A., Baulac, S., Bautista, J. F., Becker, F., Bellows, S. T., Berghuis, B., Berkovic, S. F., Bluvstein, J., Boro, A., Bridgers, J., Burgess, R., Caglayan, H., Cascino, G. D., Cavalleri, G. L., Chung, S. -K., Cieuta-Walti, C., Cloutier, V., Consalvo, D., Cossette, P., Crumrine, P., Delanty, N., Depondt, C., Desbiens, R., Devinsky, O., Dlugos, D., Epstein, M. P., Everett, K., Fiol, M., Fountain, N. B., Francis, B., French, J., Freyer, C., Friedman, D., Gambardella, A., Geller, E. B., Girard, S., Glauser, T., Glynn, S., Goldstein, D. B., Gravel, M., Haas, K., Haut, S. R., Heinzen, E. L., Helbig, I., Hildebrand, M. S., Johnson, M. R., Jorgensen, A., Joshi, S., Kanner, A., Kirsch, H. E., Klein, K. M., Knowlton, R. C., Koeleman, B. P. C., Kossoff, E. H., Krause, R., Krenn, M., Kunz, W. S., Kuzniecky, R., Langley, S. R., Leguern, E., Lehesjoki, A. -E., Lerche, H., Leu, C., Lortie, A., Lowenstein, D. H., Marson, A. G., Mebane, C., Mefford, H. C., Meloche, C., Moreau, C., Motika, P. V., Muhle, H., Moller, R. S., Nabbout, R., Nguyen, D. K., Nikanorova, M., Novotny, E. J., Nurnberg, P., Ottman, R., O'Brien, T. J., Paolicchi, J. M., Parent, J. M., Park, K., Peter, S., Petrou, S., Petrovski, S., Pickrell, W. O., Poduri, A., Radtke, R. A., Rees, M. I., Regan, B. M., Ren, Z., Sadleir, L. G., Sander, J. W., Sander, T., Scheffer, I. E., Schubert, J., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Shinnar, S., Sills, G. J., Singh, R. K., Siren, A., Sirven, J., Sisodiya, S. M., Smith, M. C., Sonsma, A. C. M., Striano, P., Sullivan, J., Thio, L. L., Thomas, R. H., Venkat, A., Vining, E. P. G., Von Allmen, G. K., Wang, Q., Weber, Y. G., Weckhuysen, S., Weisenberg, J. L., Widdess-Walsh, P., Winawer, M. R., Wolking, S., Zara, F., Zimprich, F., Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium, Department of Medical and Clinical Genetics, Medicum, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Peter, Sarah, Petrou, Steven, Petrovski, Slavé, Pickrell, William O., Poduri, Annapurna, Radtke, Rodney A., Rees, Mark I., Regan, Brigid M., Ren, Zhong, Sadleir, Lynette G., Alldredge, Brian K., Sander, Josemir W., Sander, Thomas, Scheffer, Ingrid E., Schubert, Julian, Shellhaas, Renée A., Sherr, Elliott H., Shih, Jerry J., Shinnar, Shlomo, Sills, Graeme J., Singh, Rani K., Allen, Andrew S., Siren, Auli, Sirven, Joseph, Sisodiya, Sanjay M., Smith, Michael C., Sonsma, Anja C. M., Striano, Pasquale, Sullivan, Joseph, Thio, Liu Lin, Thomas, Rhys H., Venkat, Anu, Altmüller, Janine, Vining, Eileen P. G., Von Allmen, Gretchen K., Wang, Quanli, Weber, Yvonne G., Weckhuysen, Sarah, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Wolking, Stefan, Zara, Federico, Amrom, Dina, Zimprich, Fritz, Andermann, Eva, Auce, Pauls, Avbersek, Andreja, Baulac, Stéphanie, Bautista, Jocelyn F., Becker, Felicitas, Bellows, Susannah T., Berghuis, Bianca, Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Bridgers, Joshua, Burgess, Rosemary, Caglayan, Hande, Cascino, Gregory D., Cavalleri, Gianpiero L., Chung, Seo-Kyung, Cieuta-Walti, Cécile, Cloutier, Véronique, Consalvo, Damian, Cossette, Patrick, Crumrine, Patricia, Delanty, Norman, Depondt, Chantal, Desbiens, Richard, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Everett, Kate, Fiol, Miguel, Fountain, Nathan B., Francis, Ben, French, Jacqueline, Freyer, Catharine, Friedman, Daniel, Gambardella, Antonio, Geller, Eric B., Girard, Simon, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gravel, Micheline, Haas, Kevin, Haut, Sheryl R., Heinzen, Erin L., Helbig, Ingo, Hildebrand, Michael S., Johnson, Michael R., Jorgensen, Andrea, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Klein, Karl M., Knowlton, Robert C., Koeleman, Bobby P. C., Kossoff, Eric H., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Langley, Sarah R., LeGuern, Eric, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lortie, Anne, Lowenstein, Daniel H., Marson, Anthony G., Mebane, Caroline, Mefford, Heather C., Meloche, Caroline, Moreau, Claudia, Motika, Paul V., Muhle, Hiltrud, Møller, Rikke S., Nabbout, Rima, Nguyen, Dang K., Nikanorova, Marina, Novotny, Edward J., Nürnberg, Peter, Ottman, Ruth, O'Brien, Terence J., Paolicchi, Juliann M., Parent, Jack M., and Park, Kristen

Subjects
GABA receptors, Neurology [D14] [Human health sciences], Clinical Sciences, GABA(A) receptors, GABRG2, familial epilepsy, Article, Clinical Research, Receptors, Exome Sequencing, Genetics, 2.1 Biological and endogenous factors, Humans, GGE, Genetic Predisposition to Disease, sporadic epilepsy, EpiPGX Consortium, Aetiology, gamma-Aminobutyric Acid, GABAA receptors, Epi4K Consortium, Epilepsy, Neurology & Neurosurgery, Neurologie [D14] [Sciences de la santé humaine], Generalized, GABA-A, Prevention, Human Genome, Neurosciences, 1184 Genetics, developmental biology, physiology, 3112 Neurosciences, Receptors, GABA-A, EuroEPINOMICS-CoGIE Consortium, Neurology, Case-Control Studies, Epilepsy, Generalized, Canadian Epilepsy Network, Neurology (clinical), Genetics & genetic processes [F10] [Life sciences], 3111 Biomedicine, Human medicine, Génétique & processus génétiques [F10] [Sciences du vivant], Epilepsy Phenome/Genome Project
Abstract

ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p=1.8×10-5 ), approaching study-wide significance in familial GGE (p=3.0×10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR]=3.9, 95% confidence interval [CI]=1.9-7.8, false discovery rate [FDR]-adjusted p=.0024), whereas their association with sporadic GGE had marginally lower odds (OR=3.1, 95% CI=1.3-6.7, FDR-adjusted p=.022). URVs in GABAergic pathway genes were associated with familial GGE (OR=1.8, 95% CI=1.3-2.5, FDR-adjusted p=.0024) but not with sporadic GGE (OR=1.3, 95% CI=.9-1.9, FDR-adjusted p=.19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Published
2022

10. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author

Christian E. Elger, Wolfgang Lieb, Claudia B. Catarino, Pasquale Striano, Andreja Avbersek, Daniel H. Lowenstein, Philip E. M. Smith, G. Neil Thomas, Dick Lindhout, Erin L. Heinzen, Sanjay M. Sisodiya, Orrin Devinsky, Alexander R. H. Smith, Rainer Surges, Stefan Wolking, Patrick Cossette, Annapurna Poduri, Eric B. Geller, Stacey S. Cherny, Maria Stella Vari, Peter De Jonghe, Kevin Haas, Andres Ingason, Reetta Kälviäinen, Krishna Chinthapalli, Dennis Lal, Graeme J. Sills, Martina Moerzinger, Jonathan P. Bradfield, Mark R Newton, Federico Zara, Sheryl R. Haut, Warren D. Lo, Holger Lerche, Felix Rosenow, Robert C. Knowlton, Mark McCormack, Sarah Rau, Felicitas Becker, Andre Franke, Heidi E. Kirsch, Patrick Kwan, Remi Stevelink, Rodney A. Radtke, Michele Iacomino, Faith Pangilinan, Ulrich Stephani, David F. Smith, Eva M. Reinthaler, Chantal Depondt, Hiltrud Muhle, Russell J. Buono, Alison J. Coffey, Ellen Campbell, Marvin Johnson, Bernhard J. Steinhoff, Sarah von Spiczak, Yvonne G. Weber, Ping-Wing Ng, Kerstin Hallmann, Philipp S. Reif, David Goldstein, Bettina Schmitz, Antonietta Coppola, Jerry J. Shih, Karen Oliver, Anne-Mari Kantanen, Rossana Tozzi, Markus Wolff, Albert J. Becker, Anne M. Molloy, Lisa Slattery, James L. Mills, Judith L.Z. Weisenberg, Jacqueline A. French, Lawrence C. Brody, Int League Against Epilepsy Conso, Peter Widdess-Walsh, Helle Hjalgrim, Christian Hengsbach, Christoph J. Schankin, Johan G. Eriksson, Tracy A. Glauser, Yu-Lung Lau, Larry Baum, Anna-Elina Lehesjoki, Nicole M. Walley, Josemir W. Sander, Markus M. Noethen, Simon Glynn, Jennifer Jamnadas-Khoda, Thomas Bast, Susanne Schoch, Iscia Lopes-Cendes, Doug Speed, Anja C M Sonsma, John Craig, Ingo Helbig, Marian Todaro, Gregory D. Cascino, Steven C. Schachter, Fritz Zimprich, Samuel F. Berkovic, Michael Privitera, Ben Francis, Martin Krenn, Rikke S. Møller, Eileen P.G. Vining, Martha Feucht, Bobby P. C. Koeleman, Ruben Kuzniecky, Christian Gieger, K. Meng Tan, Dalia Kasperaviciute, Pauls Auce, Gianpiero L. Cavalleri, Melanie Bahlo, Zhi Wei, Nasir Mirza, David J. Balding, Mike Smith, Liu Lin Thio, Alastair Compston, Katja E. Boysen, Gerrit-Jan de Haan, Hongsheng Gui, Hakon Hakonarson, Christopher D. Whelan, Colin P. Doherty, Youling Guo, Aarno Palotie, Wolfram S. Kunz, Slavé Petrovski, Thomas Sander, Frank Visscher, Bianca Berghuis, Costin Leu, Verena Gaus, Dennis J. Dlugos, Ingrid E. Scheffer, Alberto Malovini, Konstantin Strauch, Wanling Yang, Saskia Freytag, H. Stroink, Pak C. Sham, Norman Delanty, Terence J. O'Brien, Carolien G.F. de Kovel, Thomas U. Mayer, Anthony G Marson, Bassel Abou-Khalil, Thomas N. Ferraro, Dorothée G.A. Kasteleijn-Nolst Trenité, Roland Krause, Sarah Peter, Peter Nuernberg, Theresa Scattergood, Michael R. Sperling, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, Department of Medical and Clinical Genetics, Medicum, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Int League Against Epilepsy Conso, Abou-Khalil, Bassel, Auce, Paul, Avbersek, Andreja, Bahlo, Melanie, J Balding, David, Bast, Thoma, Baum, Larry, J Becker, Albert, Becker, Felicita, Berghuis, Bianca, F Berkovic, Samuel, E Boysen, Katja, P Bradfield, Jonathan, C Brody, Lawrence, J Buono, Russell, Campbell, Ellen, D Cascino, Gregory, B Catarino, Claudia, L Cavalleri, Gianpiero, S Cherny, Stacey, Chinthapalli, Krishna, J Coffey, Alison, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, J Craig, John, de Haan, Gerrit-Jan, De Jonghe, Peter, F de Kovel, Carolien G, Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, J Dlugos, Denni, P Doherty, Colin, E Elger, Christian, G Eriksson, Johan, N Ferraro, Thoma, Feucht, Martha, Francis, Ben, Franke, Andre, A French, Jacqueline, Freytag, Saskia, Gaus, Verena, B Geller, Eric, Gieger, Christian, Glauser, Tracy, Glynn, Simon, B Goldstein, David, Gui, Hongsheng, Guo, Youling, F Haas, Kevin, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, L Heinzen, Erin, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, André, Jamnadas-Khoda, Jennifer, R Johnson, Michael, Kälviäinen, Reetta, Kantanen, Anne-Mari, Kasperavičiūte, Dalia, Kasteleijn-Nolst Trenite, Dorothee, E Kirsch, Heidi, C Knowlton, Robert, C Koeleman, Bobby P, Krause, Roland, Krenn, Martin, S Kunz, Wolfram, Kuzniecky, Ruben, Kwan, Patrick, Lal, Denni, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, D Lo, Warren, Lopes-Cendes, Iscia, H Lowenstein, Daniel, Malovini, Alberto, G Marson, Anthony, Mayer, Thoma, Mccormack, Mark, L Mills, Jame, Mirza, Nasir, Moerzinger, Martina, S Møller, Rikke, M Molloy, Anne, Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, M Nöthen, Marku, Nürnberg, Peter, J O'Brien, Terence, L Oliver, Karen, Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slavé, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, S Reif, Philipp, M Reinthaler, Eva, Rosenow, Felix, W Sander, Josemir, Sander, Thoma, Scattergood, Theresa, C Schachter, Steven, J Schankin, Christoph, E Scheffer, Ingrid, Schmitz, Bettina, Schoch, Susanne, C Sham, Pak, J Shih, Jerry, J Sills, Graeme, M Sisodiya, Sanjay, Slattery, Lisa, Smith, Alexander, F Smith, David, C Smith, Michael, E Smith, Philip, M Sonsma, Anja C, Speed, Doug, R Sperling, Michael, J Steinhoff, Bernhard, Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Han, Surges, Rainer, Meng Tan, K, Lin Thio, Liu, Neil Thomas, G, Todaro, Marian, Tozzi, Rossana, S Vari, Maria, G Vining, Eileen P, Visscher, Frank, von Spiczak, Sarah, M Walley, Nicole, G Weber, Yvonne, Wei, Zhi, Weisenberg, Judith, D Whelan, Christopher, Widdess-Walsh, Peter, Wolff, Marku, Wolking, Stefan, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Wellcome Trust, GlaxoSmithKline Services Unlimited, Commission of the European Communities, Medical Research Council (MRC), and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
0301 basic medicine, Linkage disequilibrium, LD SCORE REGRESSION, Neurology [D14] [Human health sciences], General Physics and Astronomy, Genome-wide association study, ILAE COMMISSION, Neurodegenerative, Genome, Linkage Disequilibrium, Epilepsy, Gene Frequency, Missing heritability problem, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, International League Against Epilepsy Consortium on Complex Epilepsies, Multidisciplinary, Genetic Predisposition to Disease/genetics, Chromosome Mapping, ASSOCIATION, Epilepsy/classification, Single Nucleotide, ABSENCE, 3. Good health, Technologie de l'environnement, contrôle de la pollution, SNP HERITABILITY, Neurological, Genome-Wide Association Study/methods, Case-Control Studie, Engineering sciences. Technology, Human, Biotechnology, EXPRESSION, SUSCEPTIBILITY LOCI, Genotype, Science, Quantitative Trait Loci, 610 Medicine & health, Computational biology, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, 03 medical and health sciences, MD Multidisciplinary, medicine, Genetics, SNP, Chimie, FRONTAL-LOBE, Humans, Genetic Predisposition to Disease, Polymorphism, METAANALYSIS, Neurologie [D14] [Sciences de la santé humaine], Physique, Human Genome, Neurosciences, General Chemistry, Astronomie, medicine.disease, Genetic architecture, Brain Disorders, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, epilepsy, lcsh:Q, 3111 Biomedicine, Quantitative Trait Loci/genetics, Genome-Wide Association Study
Abstract

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

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