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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Nature Genetics, Volume 55, No. 9, Year 2023
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Description
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. © 2023, The Author(s).
Authors & Co-Authors
Chen, Siwei
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
Adesoji, Oluyomi Modupe
Germany, Koln
Universität zu Köln
Afawi, Zaid
Israel, Tel Aviv-yafo
Tel Aviv University
Andrade, Danielle M.
Canada, Toronto
University of Toronto
Annesi, Grazia
Italy, Rome
Consiglio Nazionale Delle Ricerche
Bahlo, Melanie
Australia, Melbourne
Walter and Eliza Hall Institute of Medical Research
Australia, Melbourne
University of Melbourne
Baker, Mark D.
United Kingdom, Swansea
Swansea University
Balagura, Ganna
Italy, Genoa
Università Degli Studi Di Genova
Italy, Genoa
Istituto Giannina Gaslini
Balestrini, Simona
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, Chalfont st Peter
Chalfont Centre for Epilepsy
Bartoloméi, Fabrice
France, Marseille
Ap-hm Assistance Publique - Hôpitaux de Marseille
Bast, Thomas
Germany, Kehl
Epilepsy Center Kork
Germany, Freiburg Im Breisgau
Universität Freiburg
Baykan, Betül B.
Turkey, Istanbul
Istanbul Üniversitesi
Becker, Albert Johann
Germany, Bonn
Universitätsklinikum Bonn
Becker, Felicitas
Germany, Ulm
Universität Ulm
Beydoun, Ahmad A.
Lebanon, Beirut
American University of Beirut
Bisulli, Francesca
Italy, Bologna
Istituto Delle Scienze Neurologiche Di Bologna
Italy, Bologna
Alma Mater Studiorum Università Di Bologna
Blatt, Ilan
Israel, Tel Aviv-yafo
Tel Aviv University
Israel, Tel Hashomer Tel Aviv
Chaim Sheba Medical Center Israel
Bobbili, Dheeraj Reddy
Luxembourg, Esch-sur-alzette
University of Luxembourg
Borggraefe, Ingo
Germany, Munich
Ludwig-maximilians-universität München
Bosselmann, Christian Malte
Germany, Tubingen
Eberhard Karls Universität Tübingen
Bradfield, Jonathan P.
United States, Philadelphia
The Children's Hospital of Philadelphia
Brockmann, Knut
Germany, Gottingen
Universitätsmedizin Göttingen
Buono, Russell J.
United States, Philadelphia
The Children's Hospital of Philadelphia
United States, Glassboro
Rowan University
United States, Philadelphia
Thomas Jefferson University Hospital
Busch, Robyn M.
United States, Cleveland
Cleveland Clinic Foundation
Canafoglia, Laura
Italy, Milan
Foundation Irccs Neurological Institute C. Besta
Castellotti, B.
Italy, Milan
Foundation Irccs Neurological Institute C. Besta
Cavalleri, Gianpiero L.
Ireland, Dublin
Royal College of Surgeons in Ireland
Cerrato, Felecia E.
United States, Cambridge
Massachusetts Institute of Technology
Chung, Seo Kyung
Australia, Sydney
The University of Sydney
United Kingdom, Swansea
Swansea University
Cole, Andrew J.
United States, Boston
Massachusetts General Hospital
Compston, Alastair D.
Unknown Affiliation
Coppola, Antonietta
Italy, Naples
Università Degli Studi Di Napoli Federico Ii
Davis, Lea Karatheodoris
United States, Nashville
Vanderbilt University Medical Center
Delanty, Norman
Ireland, Dublin
Royal College of Surgeons in Ireland
Ireland, Dublin
Beaumont Hospital
Depondt, Chantal
Belgium, Brussels
Université Libre de Bruxelles
Derambure, Philippe H.
France, Lille
Université de Lille
Devinsky, Orrin In
United States, New York
New York University
Dlugos, Dennis J.
United States, Philadelphia
The Children's Hospital of Philadelphia
Doherty, Colin P.
Ireland, Dublin
St James's Hospital
El-Naggar, Hany
Ireland, Dublin
Royal College of Surgeons in Ireland
Ireland, Dublin
Beaumont Hospital
Eriksson, Johan Gunnar
Finland, Helsinki
Helsinki University Hospital
Feucht, Martha
Austria, Vienna
Medizinische Universität Wien
Fortunato, Francesco
Italy, Catanzaro
Università Degli Studi Magna Graecia Di Catanzaro
Franceschetti, Silvana
Italy, Milan
Foundation Irccs Neurological Institute C. Besta
French, Jacqueline A.
United States, New York
Nyu Grossman School of Medicine
Freri, Elena
Italy, Milan
Foundation Irccs Neurological Institute C. Besta
Gagliardi, Monica
Italy, Catanzaro
Università Degli Studi Magna Graecia Di Catanzaro
Gambardella, Antonio
Italy, Catanzaro
Università Degli Studi Magna Graecia Di Catanzaro
Giangregorio, Tania
Italy, Bologna
Istituto Delle Scienze Neurologiche Di Bologna
Glauser, Tracy A.
United States, Cincinnati
Cincinnati Children's Hospital Medical Center
Goldberg, Ethan M.
United States, Philadelphia
The Children's Hospital of Philadelphia
Goldman, Alica M.
United States, Houston
Baylor College of Medicine
Granata, Tiziana
Italy, Milan
Foundation Irccs Neurological Institute C. Besta
Guerrini, Renzo
Italy, Florence
Università Degli Studi Di Firenze
Gupta, Namrata
United States, Cambridge
Massachusetts Institute of Technology
Hallmann, Kerstin
Germany, Bonn
Universität Bonn
Germany, Bonn
Life & Brain Gmbh
Helbig, Ingo
United States, Philadelphia
The Children's Hospital of Philadelphia
United States, Philadelphia
University of Pennsylvania
Germany, Kiel
Universitätsklinikum Schleswig-holstein Campus Kiel
Germany, Kiel
Christian-albrechts-universität zu Kiel
Hirose, Shinichi
Japan, Fukuoka
Fukuoka University
Hirsch, Édouard
France, Strasbourg
Les Hôpitaux Universitaires de Strasbourg
Hjalgrim, Helle
Denmark, Dianalund
Danish Epilepsy Centre, Dianalund
Denmark, Odense
Syddansk Universitet
Howrigan, Daniel P.
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
Iacomino, Michele
Italy, Genoa
Istituto Giannina Gaslini
Jehi, Lara E.
United States, Cleveland
Cleveland Clinic Foundation
Johnson, Michael R.
United Kingdom, London
Imperial College London
Kälviäinen, Reetta K. K.
Finland, Kuopio
Kuopio University Hospital
Finland, Kuopio
Itä-suomen Yliopisto
Kamatani, Yoichiro
Japan, Tokyo
The University of Tokyo
Kanaan, Moien N.
Palestine, Bethlehem
Bethlehem University
Kanai, Masahiro
United States, Cambridge
Massachusetts Institute of Technology
Japan, Suita
Graduate School of Medicine
Kantanen, Anne Mari
Finland, Kuopio
Kuopio University Hospital
Kara, Bülent
Turkey, Izmir
Kocaeli Üniversitesi
Kariuki, Symon M.
Kenya, Nairobi
Wellcome Trust Research Laboratories Nairobi
Kenya, Kilifi
Pwani University
United Kingdom, Oxford
University of Oxford
Kasperavičiũte, Dalia
United Kingdom, London
Ucl Queen Square Institute of Neurology
Kato, Mitsuhiro
Japan, Tokyo
Showa University School of Medicine
Kegele, Josua
Germany, Tubingen
Eberhard Karls Universität Tübingen
Kesim, Yeşim (Yeşim)
Turkey, Istanbul
Istanbul Üniversitesi
Khoueiry Zgheib, Nathalie Khoueiry
Lebanon, Beirut
American University of Beirut
Klein, Karl M.
Germany, Marburg
Philipps-universität Marburg
Germany, Frankfurt am Main
Goethe-universität Frankfurt am Main
Canada, Calgary
Hotchkiss Brain Institute
Kluger, Gerhard Josef
Austria, Salzburg
Paracelsus Medizinische Privatuniversitat
Knake, Susanne
Germany, Marburg
Philipps-universität Marburg
Germany, Frankfurt am Main
Goethe-universität Frankfurt am Main
Koeleman, Bobby P.C.
Netherlands, Utrecht
University Medical Center Utrecht
Korczyn, Amos D.
Israel, Tel Aviv-yafo
Tel Aviv University
Krause, Roland
Luxembourg, Esch-sur-alzette
University of Luxembourg
Krenn, Martin
Austria, Vienna
Medizinische Universität Wien
Krestel, Heinz E.
Germany, Frankfurt am Main
Goethe-universität Frankfurt am Main
Switzerland, Bern
University of Bern
United States, New Haven
Yale School of Medicine
Krey, Ilona
Germany, Leipzig
Universität Leipzig
Kurki, Mitja Ilari
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
Finland, Helsinki
Helsingin Yliopisto
Kurlemann, Gerhard
Unknown Affiliation
Kwan, Patrick
Australia, Melbourne
Royal Melbourne Hospital
Australia, Clayton
Monash University
Hong Kong, Hong Kong
Chinese University of Hong Kong
Labate, Angelo
Italy, Messina
Università Degli Studi Di Messina
Landoulsi, Zied
Luxembourg, Esch-sur-alzette
University of Luxembourg
Lau, Yu Lung
Hong Kong, Hong Kong
The University of Hong Kong
Lehesjoki, Anna Elina E.
Finland, Helsinki
Folkhälsan
Lemke, Johannes R.
Germany, Leipzig
Universität Leipzig
Lerche, Holger
Germany, Tubingen
Eberhard Karls Universität Tübingen
Lesca, Gaëtan
France, Lyon
Université de Lyon
Leu, Costin
United Kingdom, London
Ucl Queen Square Institute of Neurology
United States, Cleveland
Cleveland Clinic Foundation
United States, Cambridge
Massachusetts Institute of Technology
Lewis-Smith, David
United States, Philadelphia
The Children's Hospital of Philadelphia
United Kingdom, Newcastle
Newcastle University
United Kingdom, Newcastle
The Newcastle Upon Tyne Hospitals Nhs Foundation Trust
Licchetta, Laura
Italy, Bologna
Istituto Delle Scienze Neurologiche Di Bologna
Linnankivi, Tarja T.
Finland, Helsinki
Children's Hospital Helsinki
Finland, Helsinki
Helsingin Yliopisto
Finland, Helsinki
Helsinki University Hospital
Lopes-Cendes, Íscia Teresinha
Brazil, Campinas
Universidade Estadual de Campinas
Lowenstein, Daniel H.
United States, San Francisco
University of California, San Francisco
Madia, Francesca
Italy, Genoa
Istituto Giannina Gaslini
Marson, Anthony Guy
United Kingdom, Liverpool
University of Liverpool
May, Patrick
Luxembourg, Esch-sur-alzette
University of Luxembourg
Mei, Davide
Italy, Florence
Università Degli Studi Di Firenze
Mills, James L.
United States, Bethesda
National Institutes of Health Nih
Montomoli, Martino
Italy, Florence
Università Degli Studi Di Firenze
Mühle, Hiltrud
Germany, Kiel
Christian-albrechts-universität zu Kiel
Najm, Imad Michel
United States, Cleveland
Cleveland Clinic Foundation
Nasreddine, Wassim M.
Lebanon, Beirut
American University of Beirut
Newton, Charles R.J.C.
Kenya, Nairobi
Wellcome Trust Research Laboratories Nairobi
Kenya, Kilifi
Pwani University
United Kingdom, Oxford
University of Oxford
Nothnagel, Michael
Germany, Koln
Universität zu Köln
Germany, Koln
Uniklinik Köln
Nürnberg, Peter
Germany, Koln
Universität zu Köln
O'Brien, Terence J.
Australia, Melbourne
Royal Melbourne Hospital
Australia, Clayton
Monash University
Okada, Yukinori
Japan, Suita
Graduate School of Medicine
Japan, Yokohama
Riken Center for Integrative Medical Sciences
Ozkara, Cigdem
Turkey, Istanbul
Istanbul University-cerrahpasa
Palotie, Aarno V.
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
Finland, Helsinki
Helsingin Yliopisto
Papacostas, Savvas S.
Cyprus, Nicosia
Cyprus Institute of Neurology and Genetics
Parrini, Elena
Italy, Florence
Università Degli Studi Di Firenze
Pato, Carlos N.
United States, Newark
Rutgers new Jersey Medical School
Pato, Michèle T.
United States, Newark
Rutgers new Jersey Medical School
Pendziwiat, Manuela
Germany, Kiel
Universitätsklinikum Schleswig-holstein Campus Kiel
Germany, Kiel
Christian-albrechts-universität zu Kiel
Petrovski, Slavé D.Sign©
Australia, Melbourne
Royal Melbourne Hospital
United Kingdom, Cambridge
Astrazeneca
Pickrell, William Owen
United Kingdom, Swansea
Swansea University
United Kingdom, Port Talbot
Swansea Bay University Health Board
Pippucci, Tommaso
Italy, Bologna
Irccs Azienda Ospedaliero-universitaria Di Bologna
Poduri, Anna H.
United States, Boston
Boston Children's Hospital
Rees, Mark I.
United Kingdom, Swansea
Swansea University
Australia, Sydney
The University of Sydney
Regan, Brigid M.
Australia, Melbourne
Austin Health
Reif, Philipp Sebastian
Germany, Marburg
Philipps-universität Marburg
Germany, Frankfurt am Main
Goethe-universität Frankfurt am Main
Riva, Antonella
Italy, Genoa
Università Degli Studi Di Genova
Italy, Genoa
Istituto Giannina Gaslini
Rosenow, Felix
Germany, Marburg
Philipps-universität Marburg
Germany, Frankfurt am Main
Goethe-universität Frankfurt am Main
Ryvlin, Philippe
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Sadleir, Lynette Grant
New Zealand, Dunedin
University of Otago
Sander, Josemir W.A.S.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, Chalfont st Peter
Chalfont Centre for Epilepsy
Netherlands, Heemstede
Stichting Epilepsie Instellingen Nederland
Scala, Marcello
Italy, Genoa
Università Degli Studi Di Genova
Italy, Genoa
Istituto Giannina Gaslini
Schoch, Susanne
Germany, Bonn
Universitätsklinikum Bonn
Schubert-Bast, Susanne
Germany, Frankfurt am Main
Goethe-universität Frankfurt am Main
Sheidley, Beth Rosen
United States, Boston
Boston Children's Hospital
Sisodiya, Sanjay M.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, Chalfont st Peter
Chalfont Centre for Epilepsy
Sperling, Michael R.
United States, Philadelphia
Thomas Jefferson University
Stefánsson, Hreinn
Iceland, Reykjavik
Decode Genetics
Stefánsson, Kari
Iceland, Reykjavik
Decode Genetics
Steinhoff, Bernhard Jochen
Germany, Kehl
Epilepsy Center Kork
Germany, Freiburg Im Breisgau
Universität Freiburg
Stephani, Ulrich
Germany, Kiel
Christian-albrechts-universität zu Kiel
Striano, Pasquale
Italy, Genoa
Università Degli Studi Di Genova
Italy, Genoa
Istituto Giannina Gaslini
Surges, Rainer
Germany, Bonn
Universität Bonn
Thomas, Rhys Huw
United Kingdom, Newcastle
Newcastle University
United Kingdom, Newcastle
The Newcastle Upon Tyne Hospitals Nhs Foundation Trust
Tinuper, Paolo
Italy, Bologna
Istituto Delle Scienze Neurologiche Di Bologna
Italy, Bologna
Alma Mater Studiorum Università Di Bologna
Tsai, Menghan
Taiwan, Taipei
Chang Gung Memorial Hospital
Valton, Luc
France, Toulouse
Université Toulouse Iii - Paul Sabatier
Vetro, Annalisa
Italy, Florence
Università Degli Studi Di Firenze
Wagner, Ryan G.
South Africa, Johannesburg
University of the Witwatersrand Faculty of Health Sciences
Weber, Yvonne G.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Aachen
University of Aachen
Weckhuysen, Sarah
Belgium, Ghent
Vlaams Instituut Voor Biotechnologie
Belgium, Edegem
Universitair Ziekenhuis Antwerpen
Belgium, Antwerpen
Universiteit Antwerpen
Wolff, Markus
Germany, Berlin
Vivantes Humboldt-klinikum
Yapici, Zuhal
Turkey, Istanbul
Istanbul Üniversitesi
Zagaglia, Sara
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, Chalfont st Peter
Chalfont Centre for Epilepsy
Zimprich, Fritz
Austria, Vienna
Medizinische Universität Wien
Statistics
Citations: 3
Authors: 158
Affiliations: 166
Identifiers
Doi:
10.1038/s41588-023-01485-w
ISSN:
10614036
Research Areas
Genetics And Genomics
Study Approach
Systematic review