Projects per year
Abstract
Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 1471-1482 |
| Number of pages | 12 |
| Journal | Nature Genetics |
| Volume | 55 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sept 2023 |
Projects
-
Human Epilepsy: Understanding biology to improve outcomes
Berkovic, S. F., Jackson, G. D., Gecz, J., Connelly, A., Scheffer, I. E., O'Brien, T., Calamante, F., Petrou, S. & Reid, C. A.
National Health and Medical Research Council (NHMRC) (Australia)
23/04/18 → 31/12/20
Project: Research
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International League Against Epilepsy Consortium on Complex Epilepsies (2023). GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nature Genetics, 55(9), 1471-1482. https://doi.org/10.1038/s41588-023-01485-w
International League Against Epilepsy Consortium on Complex Epilepsies. / GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. In: Nature Genetics. 2023 ; Vol. 55, No. 9. pp. 1471-1482.
@article{f84976fbef3d438a9960e23b5c7c1ceb,
title = "GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture",
abstract = "Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.",
author = "Remi Stevelink and Ciar{\'a}n Campbell and Siwei Chen and Bassel Abou-Khalil and Adesoji, {Oluyomi M.} and Zaid Afawi and Elisabetta Amadori and Alison Anderson and Joseph Anderson and Andrade, {Danielle M.} and Grazia Annesi and Pauls Auce and Andreja Avbersek and Melanie Bahlo and Baker, {Mark D.} and Ganna Balagura and Simona Balestrini and Carmen Barba and Karen Barboza and Fabrice Bartolomei and Thomas Bast and Larry Baum and Tobias Baumgartner and Bet{\"u}l Baykan and Nerses Bebek and Becker, {Albert J.} and Felicitas Becker and Bennett, {Caitlin A.} and Bianca Berghuis and Berkovic, {Samuel F.} and Ahmad Beydoun and Claudia Bianchini and Francesca Bisulli and Ilan Blatt and Bobbili, {Dheeraj R.} and Ingo Borggraefe and Christian Bosselmann and Vera Braatz and Bradfield, {Jonathan P.} and Knut Brockmann and Brody, {Lawrence C.} and Buono, {Russell J.} and Busch, {Robyn M.} and Hande Caglayan and Ellen Campbell and Laura Canafoglia and Christina Canavati and Cascino, {Gregory D.} and Barbara Castellotti and Catarino, {Claudia B.} and Cavalleri, {Gianpiero L.} and Felecia Cerrato and Francine Chassoux and Cherny, {Stacey S.} and Cheung, {Ching Lung} and Krishna Chinthapalli and Chou, {I. Jun} and Chung, {Seo Kyung} and Claire Churchhouse and Clark, {Peggy O.} and Cole, {Andrew J.} and Alastair Compston and Antonietta Coppola and Mahgenn Cosico and Patrick Cossette and Craig, {John J.} and Caroline Cusick and Daly, {Mark J.} and Davis, {Lea K.} and {de Haan}, {Gerrit Jan} and Norman Delanty and Chantal Depondt and Philippe Derambure and Orrin Devinsky and {Di Vito}, Lidia and Dlugos, {Dennis J.} and Viola Doccini and Doherty, {Colin P.} and Hany El-Naggar and Elger, {Christian E.} and Ellis, {Colin A.} and Eriksson, {Johan G.} and Annika Faucon and Feng, {Yen Chen A.} and Lisa Ferguson and Ferraro, {Thomas N.} and Lorenzo Ferri and Martha Feucht and Mark Fitzgerald and Beata Fonferko-Shadrach and Francesco Fortunato and Silvana Franceschetti and Andre Franke and French, {Jacqueline A.} and Elena Freri and Monica Gagliardi and Antonio Gambardella and Geller, {Eric B.} and Tania Giangregorio and Leif Gjerstad and Tracy Glauser and Ethan Goldberg and Alicia Goldman and Tiziana Granata and Greenberg, {David A.} and Renzo Guerrini and Namrata Gupta and Haas, {Kevin F.} and Hakon Hakonarson and Kerstin Hallmann and Emadeldin Hassanin and Manu Hegde and Heinzen, {Erin L.} and Ingo Helbig and Christian Hengsbach and Heyne, {Henrike O.} and Shinichi Hirose and Edouard Hirsch and Helle Hjalgrim and Howrigan, {Daniel P.} and Donald Hucks and Hung, {Po Cheng} and Michele Iacomino and Imbach, {Lukas L.} and Yushi Inoue and Atsushi Ishii and Jennifer Jamnadas-Khoda and Lara Jehi and Johnson, {Michael R.} and Reetta K{\"a}lvi{\"a}inen and Yoichiro Kamatani and Moien Kanaan and Masahiro Kanai and Kantanen, {Anne Mari} and B{\"u}lent Kara and Kariuki, {Symon M.} and Dalia Kasperavi{\v c}iūte and {Kasteleijn-Nolst Trenite}, Dorothee and Mitsuhiro Kato and Josua Kegele and Ye{\c s}im Kesim and Nathalie Khoueiry-Zgheib and Chontelle King and Kirsch, {Heidi E.} and Klein, {Karl M.} and Gerhard Kluger and Susanne Knake and Knowlton, {Robert C.} and Koeleman, {Bobby P.C.} and Korczyn, {Amos D.} and Andreas Koupparis and Ioanna Kousiappa and Roland Krause and Martin Krenn and Heinz Krestel and Ilona Krey and Kunz, {Wolfram S.} and Kurki, {Mitja I.} and Gerhard Kurlemann and Ruben Kuzniecky and Patrick Kwan and Angelo Labate and Austin Lacey and Dennis Lal and Zied Landoulsi and Lau, {Yu Lung} and Stephen Lauxmann and Leech, {Stephanie L.} and Lehesjoki, {Anna Elina} and Lemke, {Johannes R.} and Holger Lerche and Gaetan Lesca and Costin Leu and Naomi Lewin and David Lewis-Smith and Li, {Gloria H.Y.} and Li, {Qingqin S.} and Laura Licchetta and Lin, {Kuang Lin} and Dick Lindhout and Tarja Linnankivi and Iscia Lopes-Cendes and Lowenstein, {Daniel H.} and Lui, {Colin H.T.} and Francesca Madia and Sigurdur Magnusson and Marson, {Anthony G.} and Patrick May and McGraw, {Christopher M.} and Davide Mei and Mills, {James L.} and Raffaella Minardi and Nasir Mirza and M{\o}ller, {Rikke S.} and Molloy, {Anne M.} and Martino Montomoli and Barbara Mostacci and Lorenzo Muccioli and Hiltrud Muhle and Karen M{\"u}ller-Schl{\"u}ter and Najm, {Imad M.} and Wassim Nasreddine and Neale, {Benjamin M.} and Bernd Neubauer and Newton, {Charles R.J.C.} and N{\"o}then, {Markus M.} and Michael Nothnagel and Peter N{\"u}rnberg and O{\textquoteright}Brien, {Terence J.} and Yukinori Okada and El{\'i}as {\'O}lafsson and Oliver, {Karen L.} and {\c C}iğdem {\"O}zkara and Aarno Palotie and Faith Pangilinan and Papacostas, {Savvas S.} and Elena Parrini and Pato, {Carlos N.} and Pato, {Michele T.} and Manuela Pendziwiat and Slav{\'e} Petrovski and Pickrell, {William O.} and Rebecca Pinsky and Tommaso Pippucci and Annapurna Poduri and Federica Pondrelli and Powell, {Rob H.W.} and Michael Privitera and Annika Rademacher and Rodney Radtke and Francesca Ragona and Sarah Rau and Rees, {Mark I.} and Regan, {Brigid M.} and Reif, {Philipp S.} and Sylvain Rhelms and Antonella Riva and Felix Rosenow and Philippe Ryvlin and Anni Saarela and Sadleir, {Lynette G.} and Sander, {Josemir W.} and Thomas Sander and Marcello Scala and Theresa Scattergood and Schachter, {Steven C.} and Schankin, {Christoph J.} and Scheffer, {Ingrid E.} and Bettina Schmitz and Marian Todaro and {International League Against Epilepsy Consortium on Complex Epilepsies}",
note = "Funding Information: This study received support from Science Foundation Ireland (SFI; 16/RC/3948), cofunded under the European Regional Development Fund, the Research Unit FOR-2715 of the German Research Foundation (MN: NO755/6-1 and NO755/13-1), from Wellcome Trust (grant 084730), European Union{\textquoteright}s Seventh Framework Program (FP7/2007-2013) under grant agreement 279062 (EpiPGX), The Muir Maxwell Trust and the Epilepsy Society, UK and Fonds National de la Recherche Luxembourg (Research Unit FOR-2715, FNR grant INTER/DFG/21/16394868 MechEPI2) to P.M. and R. Krause. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the NIHR Biomedical Research Centers funding scheme. Further support was received by a {\textquoteleft}Vrienden WKZ{\textquoteright} fund 1616091 (MING) to R. Stevelink and B.P.C.K., a National Health and Medical Research Council (NHMRC) of Australia Program Grant (1091593) to S.F.B. and I.E.S. and an NHMRC Investigator grant (APP1195236) to M.B. The Australian Government Research Training Program Scholarship (APP533086) provided by the Australian Commonwealth Government and the University of Melbourne supports K.L.O., a Wellcome Clinical Ph.D. Fellowship on the 4Ward North program (203914/Z/16/Z) supported D.L.-S., the UKRI MRC award MR/S02638X/1 and the NIHR Imperial Biomedical Research Center (BRC) support M.R.J., and Funda{\c c}{\~a}o de Amparo {\`a} Pesquisa do Estado de S{\~a}o Paulo (FAPESP), Brazil (grant 2013/07559-3) supported I.L.-C. The funding bodies had no role in the study design, data collection, analysis and interpretation, or in writing the manuscript. Funding Information: We thank the Epi25 principal investigators, local staff from individual cohorts and all patients with epilepsy who participated in research studies at local centers for making possible this global collaboration and resource to advance epilepsy genetics research. This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI), The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung and Blood Institute (NHLBI). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, were supported by NHGRI grant UM1 HG008895 (PIs: E. Lander, S. Gabriel, M. Daly, S. Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI under grant 5U01HG009088-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the Stanley Center for Psychiatric Research at the Broad Institute for supporting the genomic data generation efforts as well as the aggregation of control samples and cohorts to contribute to the Epi25 GWAS analyses. In particular, the Genomic Psychiatry Cohort controls were genotyped on the GSA-MD v1.0 by the Broad Genomics Platform with funding from NIH grant U01MH105641 and the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard. The FINRISK controls were part of the FINRISK studies supported by the THL (formerly KTL: National Public Health Institute) through budgetary funds from the government, with additional funding from institutions such as the Academy of Finland, the European Union, ministries and national and international foundations and societies to support specific research purposes. The collection of the Hong Kong Osteoporosis Study (HKOS) control samples was funded by the Bone Health Fund and Research Grants Council—Early Career Scheme (project 27100416). Other control datasets included IBD NIDDK and samples from the Mass General Brigham (MGB) Biobank available from dbGaP under study accession number phs002018.v1.p1. Funding Information: G.L.C. is in receipt of research funding from Congenica and Janssen Pharmaceuticals and has conducted consultancy for Ono Pharmaceuticals. S.F.B. received funding from UCB Pharma and Eisai and has been a consultant for Praxis Precision Medicines and Sequiris. Q.S.L. is an employee of Janssen Research & Development, LLC and a shareholder in Johnson & Johnson, which is the parent company of the Janssen companies. B.M.N. currently serves as a member of the scientific advisory board at Deep Genomics and Neumora (previously RBNC) and as a consultant for Camp4 Therapeutics. S.P. is an employee and shareholder of AstraZeneca. U.U., S.M., H. Stefansson and K.S. are employees of deCODE genetics/Amgen. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = sep,
doi = "10.1038/s41588-023-01485-w",
language = "English",
volume = "55",
pages = "1471--1482",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "9",
}
International League Against Epilepsy Consortium on Complex Epilepsies 2023, 'GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture', Nature Genetics, vol. 55, no. 9, pp. 1471-1482. https://doi.org/10.1038/s41588-023-01485-w
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. / International League Against Epilepsy Consortium on Complex Epilepsies.
In: Nature Genetics, Vol. 55, No. 9, 09.2023, p. 1471-1482.
In: Nature Genetics, Vol. 55, No. 9, 09.2023, p. 1471-1482.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
AU - Stevelink, Remi
AU - Campbell, Ciarán
AU - Chen, Siwei
AU - Abou-Khalil, Bassel
AU - Adesoji, Oluyomi M.
AU - Afawi, Zaid
AU - Amadori, Elisabetta
AU - Anderson, Alison
AU - Anderson, Joseph
AU - Andrade, Danielle M.
AU - Annesi, Grazia
AU - Auce, Pauls
AU - Avbersek, Andreja
AU - Bahlo, Melanie
AU - Baker, Mark D.
AU - Balagura, Ganna
AU - Balestrini, Simona
AU - Barba, Carmen
AU - Barboza, Karen
AU - Bartolomei, Fabrice
AU - Bast, Thomas
AU - Baum, Larry
AU - Baumgartner, Tobias
AU - Baykan, Betül
AU - Bebek, Nerses
AU - Becker, Albert J.
AU - Becker, Felicitas
AU - Bennett, Caitlin A.
AU - Berghuis, Bianca
AU - Berkovic, Samuel F.
AU - Beydoun, Ahmad
AU - Bianchini, Claudia
AU - Bisulli, Francesca
AU - Blatt, Ilan
AU - Bobbili, Dheeraj R.
AU - Borggraefe, Ingo
AU - Bosselmann, Christian
AU - Braatz, Vera
AU - Bradfield, Jonathan P.
AU - Brockmann, Knut
AU - Brody, Lawrence C.
AU - Buono, Russell J.
AU - Busch, Robyn M.
AU - Caglayan, Hande
AU - Campbell, Ellen
AU - Canafoglia, Laura
AU - Canavati, Christina
AU - Cascino, Gregory D.
AU - Castellotti, Barbara
AU - Catarino, Claudia B.
AU - Cavalleri, Gianpiero L.
AU - Cerrato, Felecia
AU - Chassoux, Francine
AU - Cherny, Stacey S.
AU - Cheung, Ching Lung
AU - Chinthapalli, Krishna
AU - Chou, I. Jun
AU - Chung, Seo Kyung
AU - Churchhouse, Claire
AU - Clark, Peggy O.
AU - Cole, Andrew J.
AU - Compston, Alastair
AU - Coppola, Antonietta
AU - Cosico, Mahgenn
AU - Cossette, Patrick
AU - Craig, John J.
AU - Cusick, Caroline
AU - Daly, Mark J.
AU - Davis, Lea K.
AU - de Haan, Gerrit Jan
AU - Delanty, Norman
AU - Depondt, Chantal
AU - Derambure, Philippe
AU - Devinsky, Orrin
AU - Di Vito, Lidia
AU - Dlugos, Dennis J.
AU - Doccini, Viola
AU - Doherty, Colin P.
AU - El-Naggar, Hany
AU - Elger, Christian E.
AU - Ellis, Colin A.
AU - Eriksson, Johan G.
AU - Faucon, Annika
AU - Feng, Yen Chen A.
AU - Ferguson, Lisa
AU - Ferraro, Thomas N.
AU - Ferri, Lorenzo
AU - Feucht, Martha
AU - Fitzgerald, Mark
AU - Fonferko-Shadrach, Beata
AU - Fortunato, Francesco
AU - Franceschetti, Silvana
AU - Franke, Andre
AU - French, Jacqueline A.
AU - Freri, Elena
AU - Gagliardi, Monica
AU - Gambardella, Antonio
AU - Geller, Eric B.
AU - Giangregorio, Tania
AU - Gjerstad, Leif
AU - Glauser, Tracy
AU - Goldberg, Ethan
AU - Goldman, Alicia
AU - Granata, Tiziana
AU - Greenberg, David A.
AU - Guerrini, Renzo
AU - Gupta, Namrata
AU - Haas, Kevin F.
AU - Hakonarson, Hakon
AU - Hallmann, Kerstin
AU - Hassanin, Emadeldin
AU - Hegde, Manu
AU - Heinzen, Erin L.
AU - Helbig, Ingo
AU - Hengsbach, Christian
AU - Heyne, Henrike O.
AU - Hirose, Shinichi
AU - Hirsch, Edouard
AU - Hjalgrim, Helle
AU - Howrigan, Daniel P.
AU - Hucks, Donald
AU - Hung, Po Cheng
AU - Iacomino, Michele
AU - Imbach, Lukas L.
AU - Inoue, Yushi
AU - Ishii, Atsushi
AU - Jamnadas-Khoda, Jennifer
AU - Jehi, Lara
AU - Johnson, Michael R.
AU - Kälviäinen, Reetta
AU - Kamatani, Yoichiro
AU - Kanaan, Moien
AU - Kanai, Masahiro
AU - Kantanen, Anne Mari
AU - Kara, Bülent
AU - Kariuki, Symon M.
AU - Kasperavičiūte, Dalia
AU - Kasteleijn-Nolst Trenite, Dorothee
AU - Kato, Mitsuhiro
AU - Kegele, Josua
AU - Kesim, Yeşim
AU - Khoueiry-Zgheib, Nathalie
AU - King, Chontelle
AU - Kirsch, Heidi E.
AU - Klein, Karl M.
AU - Kluger, Gerhard
AU - Knake, Susanne
AU - Knowlton, Robert C.
AU - Koeleman, Bobby P.C.
AU - Korczyn, Amos D.
AU - Koupparis, Andreas
AU - Kousiappa, Ioanna
AU - Krause, Roland
AU - Krenn, Martin
AU - Krestel, Heinz
AU - Krey, Ilona
AU - Kunz, Wolfram S.
AU - Kurki, Mitja I.
AU - Kurlemann, Gerhard
AU - Kuzniecky, Ruben
AU - Kwan, Patrick
AU - Labate, Angelo
AU - Lacey, Austin
AU - Lal, Dennis
AU - Landoulsi, Zied
AU - Lau, Yu Lung
AU - Lauxmann, Stephen
AU - Leech, Stephanie L.
AU - Lehesjoki, Anna Elina
AU - Lemke, Johannes R.
AU - Lerche, Holger
AU - Lesca, Gaetan
AU - Leu, Costin
AU - Lewin, Naomi
AU - Lewis-Smith, David
AU - Li, Gloria H.Y.
AU - Li, Qingqin S.
AU - Licchetta, Laura
AU - Lin, Kuang Lin
AU - Lindhout, Dick
AU - Linnankivi, Tarja
AU - Lopes-Cendes, Iscia
AU - Lowenstein, Daniel H.
AU - Lui, Colin H.T.
AU - Madia, Francesca
AU - Magnusson, Sigurdur
AU - Marson, Anthony G.
AU - May, Patrick
AU - McGraw, Christopher M.
AU - Mei, Davide
AU - Mills, James L.
AU - Minardi, Raffaella
AU - Mirza, Nasir
AU - Møller, Rikke S.
AU - Molloy, Anne M.
AU - Montomoli, Martino
AU - Mostacci, Barbara
AU - Muccioli, Lorenzo
AU - Muhle, Hiltrud
AU - Müller-Schlüter, Karen
AU - Najm, Imad M.
AU - Nasreddine, Wassim
AU - Neale, Benjamin M.
AU - Neubauer, Bernd
AU - Newton, Charles R.J.C.
AU - Nöthen, Markus M.
AU - Nothnagel, Michael
AU - Nürnberg, Peter
AU - O’Brien, Terence J.
AU - Okada, Yukinori
AU - Ólafsson, Elías
AU - Oliver, Karen L.
AU - Özkara, Çiğdem
AU - Palotie, Aarno
AU - Pangilinan, Faith
AU - Papacostas, Savvas S.
AU - Parrini, Elena
AU - Pato, Carlos N.
AU - Pato, Michele T.
AU - Pendziwiat, Manuela
AU - Petrovski, Slavé
AU - Pickrell, William O.
AU - Pinsky, Rebecca
AU - Pippucci, Tommaso
AU - Poduri, Annapurna
AU - Pondrelli, Federica
AU - Powell, Rob H.W.
AU - Privitera, Michael
AU - Rademacher, Annika
AU - Radtke, Rodney
AU - Ragona, Francesca
AU - Rau, Sarah
AU - Rees, Mark I.
AU - Regan, Brigid M.
AU - Reif, Philipp S.
AU - Rhelms, Sylvain
AU - Riva, Antonella
AU - Rosenow, Felix
AU - Ryvlin, Philippe
AU - Saarela, Anni
AU - Sadleir, Lynette G.
AU - Sander, Josemir W.
AU - Sander, Thomas
AU - Scala, Marcello
AU - Scattergood, Theresa
AU - Schachter, Steven C.
AU - Schankin, Christoph J.
AU - Scheffer, Ingrid E.
AU - Schmitz, Bettina
AU - Todaro, Marian
AU - International League Against Epilepsy Consortium on Complex Epilepsies
N1 - Funding Information: This study received support from Science Foundation Ireland (SFI; 16/RC/3948), cofunded under the European Regional Development Fund, the Research Unit FOR-2715 of the German Research Foundation (MN: NO755/6-1 and NO755/13-1), from Wellcome Trust (grant 084730), European Union’s Seventh Framework Program (FP7/2007-2013) under grant agreement 279062 (EpiPGX), The Muir Maxwell Trust and the Epilepsy Society, UK and Fonds National de la Recherche Luxembourg (Research Unit FOR-2715, FNR grant INTER/DFG/21/16394868 MechEPI2) to P.M. and R. Krause. Part of this work was undertaken at University College London Hospitals, which received a proportion of funding from the NIHR Biomedical Research Centers funding scheme. Further support was received by a ‘Vrienden WKZ’ fund 1616091 (MING) to R. Stevelink and B.P.C.K., a National Health and Medical Research Council (NHMRC) of Australia Program Grant (1091593) to S.F.B. and I.E.S. and an NHMRC Investigator grant (APP1195236) to M.B. The Australian Government Research Training Program Scholarship (APP533086) provided by the Australian Commonwealth Government and the University of Melbourne supports K.L.O., a Wellcome Clinical Ph.D. Fellowship on the 4Ward North program (203914/Z/16/Z) supported D.L.-S., the UKRI MRC award MR/S02638X/1 and the NIHR Imperial Biomedical Research Center (BRC) support M.R.J., and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil (grant 2013/07559-3) supported I.L.-C. The funding bodies had no role in the study design, data collection, analysis and interpretation, or in writing the manuscript. Funding Information: We thank the Epi25 principal investigators, local staff from individual cohorts and all patients with epilepsy who participated in research studies at local centers for making possible this global collaboration and resource to advance epilepsy genetics research. This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI), The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung and Blood Institute (NHLBI). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, were supported by NHGRI grant UM1 HG008895 (PIs: E. Lander, S. Gabriel, M. Daly, S. Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI under grant 5U01HG009088-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the Stanley Center for Psychiatric Research at the Broad Institute for supporting the genomic data generation efforts as well as the aggregation of control samples and cohorts to contribute to the Epi25 GWAS analyses. In particular, the Genomic Psychiatry Cohort controls were genotyped on the GSA-MD v1.0 by the Broad Genomics Platform with funding from NIH grant U01MH105641 and the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard. The FINRISK controls were part of the FINRISK studies supported by the THL (formerly KTL: National Public Health Institute) through budgetary funds from the government, with additional funding from institutions such as the Academy of Finland, the European Union, ministries and national and international foundations and societies to support specific research purposes. The collection of the Hong Kong Osteoporosis Study (HKOS) control samples was funded by the Bone Health Fund and Research Grants Council—Early Career Scheme (project 27100416). Other control datasets included IBD NIDDK and samples from the Mass General Brigham (MGB) Biobank available from dbGaP under study accession number phs002018.v1.p1. Funding Information: G.L.C. is in receipt of research funding from Congenica and Janssen Pharmaceuticals and has conducted consultancy for Ono Pharmaceuticals. S.F.B. received funding from UCB Pharma and Eisai and has been a consultant for Praxis Precision Medicines and Sequiris. Q.S.L. is an employee of Janssen Research & Development, LLC and a shareholder in Johnson & Johnson, which is the parent company of the Janssen companies. B.M.N. currently serves as a member of the scientific advisory board at Deep Genomics and Neumora (previously RBNC) and as a consultant for Camp4 Therapeutics. S.P. is an employee and shareholder of AstraZeneca. U.U., S.M., H. Stefansson and K.S. are employees of deCODE genetics/Amgen. Publisher Copyright: © 2023, The Author(s).
PY - 2023/9
Y1 - 2023/9
N2 - Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
AB - Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
UR - http://www.scopus.com/inward/record.url?scp=85169457451&partnerID=8YFLogxK
U2 - 10.1038/s41588-023-01485-w
DO - 10.1038/s41588-023-01485-w
M3 - Article
C2 - 37653029
AN - SCOPUS:85169457451
SN - 1061-4036
VL - 55
SP - 1471
EP - 1482
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -
International League Against Epilepsy Consortium on Complex Epilepsies. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nature Genetics. 2023 Sept;55(9):1471-1482. doi: 10.1038/s41588-023-01485-w