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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), Remi Stevelink, Ciarán Campbell, Siwei Chen, Bassel Abou-Khalil, Oluyomi M. Adesoji, Zaid Afawi, Elisabetta Amadori, Alison Anderson, Joseph Anderson, Danielle M. Andrade, Grazia Annesi, Pauls Auce, Andreja Avbersek, Melanie Bahlo, Mark Baker, Ganna Balagura, Simona Balestrini, Carmen Barba, Karen Barboza, Fabrice Bartolomei, Thomas Bast, Larry Baum, Tobias Baumgartner, Betül Baykan, Nerses Bebek, Albert J. Becker, Felicitas Becker, Caitlin A. Bennett, Bianca Berghuis, Samuel F. Berkovic, Ahmad Beydoun, Claudia Bianchini, Francesca Bisulli, Ilan Blatt, Dheeraj R. Bobbili, Ingo Borggraefe, Christian Bosselmann, Vera Braatz, Jonathan P. Bradfield, Knut Brockmann, Lawrence C. Brody, Russell J. Buono, Robyn M. Busch, Hande Caglayan, Ellen Campbell, Laura Canafoglia, Christina Canavati, Gregory D. Cascino, Barbara Castellotti, Claudia B. Catarino, Gianpiero L. Cavalleri, Felecia Cerrato, Francine Chassoux, Stacey S. Cherny, Ching-Lung Cheung, Krishna Chinthapalli, I-Jun Chou, Seo-Kyung Chung, Claire Churchhouse, Peggy O. Clark, Andrew J. Cole, Alastair Compston, Antonietta Coppola, Mahgenn Cosico, Patrick Cossette, John J. Craig, Caroline Cusick, Mark J. Daly, Lea K. Davis, Gerrit-Jan de Haan, Norman Delanty, Chantal Depondt, Philippe Derambure, Orrin Devinsky, Lidia Di Vito, Dennis J. Dlugos, Viola Doccini, Colin P. Doherty, Hany El-Naggar, Christian E. Elger, Colin A. Ellis, Johan G. Eriksson, Annika Faucon, Yen-Chen A. Feng, Lisa Ferguson, Thomas N. Ferraro, Lorenzo Ferri, Martha Feucht, Mark Fitzgerald, Beata Fonferko-Shadrach, Francesco Fortunato, Silvana Franceschetti, Andre Franke, Jacqueline A. French, Elena Freri, Monica Gagliardi, Antonio Gambardella, Eric B. Geller, Tania Giangregorio, Leif Gjerstad, Tracy Glauser, Ethan Goldberg, Alicia Goldman, Tiziana Granata, David A. Greenberg, Renzo Guerrini, Namrata Gupta, Kevin F. Haas, Hakon Hakonarson, Kerstin Hallmann, Emadeldin Hassanin, Manu Hegde, Erin L. Heinzen, Ingo Helbig, Christian Hengsbach, Henrike O. Heyne, Shinichi Hirose, Edouard Hirsch, Helle Hjalgrim, Daniel P. Howrigan, Donald Hucks, Po-Cheng Hung, Michele Iacomino, Lukas L. Imbach, Yushi Inoue, Atsushi Ishii, Jennifer Jamnadas-Khoda, Lara Jehi, Michael R. Johnson, Reetta Kälviäinen, Yoichiro Kamatani, Moien Kanaan, Masahiro Kanai, Anne-Mari Kantanen, Bülent Kara, Symon M. Kariuki, Dalia Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Mitsuhiro Kato, Josua Kegele, Yeşim Kesim, Nathalie Khoueiry-Zgheib, Chontelle King, Heidi E. Kirsch, Karl M. Klein, Gerhard Kluger, Susanne Knake, Robert C. Knowlton, Bobby P. C. Koeleman, Amos D. Korczyn, Andreas Koupparis, Ioanna Kousiappa, Roland Krause, Martin Krenn, Heinz Krestel, Ilona Krey, Wolfram S. Kunz, Mitja I. Kurki, Gerhard Kurlemann, Ruben Kuzniecky, Patrick Kwan, Angelo Labate, Austin Lacey, Dennis Lal, Zied Landoulsi, Yu-Lung Lau, Stephen Lauxmann, Stephanie L. Leech, Anna-Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Gaetan Lesca, Costin Leu, Naomi Lewin, David Lewis-Smith, Gloria H.-Y. Li, Qingqin S. Li, Laura Licchetta, Kuang-Lin Lin, Dick Lindhout, Tarja Linnankivi, Iscia Lopes-Cendes, Daniel H. Lowenstein, Colin H. T. Lui, Francesca Madia, Sigurdur Magnusson, Anthony G. Marson, Patrick May, Christopher M. McGraw, Davide Mei, James L. Mills, Raffaella Minardi, Nasir Mirza, Rikke S. Møller, Anne M. Molloy, Martino Montomoli, Barbara Mostacci, Lorenzo Muccioli, Hiltrud Muhle, Karen Müller-Schlüter, Imad M. Najm, Wassim Nasreddine, Benjamin M. Neale, Bernd Neubauer, Charles R. J. C. Newton, Markus M. Nöthen, Michael Nothnagel, Peter Nürnberg, Terence J. O’Brien, Yukinori Okada, Elías Ólafsson, Karen L. Oliver, Çiğdem Özkara, Aarno Palotie, Faith Pangilinan, Savvas S. Papacostas, Elena Parrini, Carlos N. Pato, Michele T. Pato, Manuela Pendziwiat, Slavé Petrovski, William O. Pickrell, Rebecca Pinsky, Tommaso Pippucci, Annapurna Poduri, Federica Pondrelli, Rob H. W. Powell, Michael Privitera, Annika Rademacher, Rodney Radtke, Francesca Ragona, Sarah Rau, Mark I. Rees, Brigid M. Regan, Philipp S. Reif, Sylvain Rhelms, Antonella Riva, Felix Rosenow, Philippe Ryvlin, Anni Saarela, Lynette G. Sadleir, Josemir W. Sander, Thomas Sander, Marcello Scala, Theresa Scattergood, Steven C. Schachter, Christoph J. Schankin, Ingrid E. Scheffer, Bettina Schmitz, Susanne Schoch, Susanne Schubert-Bast, Andreas Schulze-Bonhage, Paolo Scudieri, Pak Sham, Beth R. Sheidley, Jerry J. Shih, Graeme J. Sills, Sanjay M. Sisodiya, Michael C. Smith, Philip E. Smith, Anja C. M. Sonsma, Doug Speed, Michael R. Sperling, Hreinn Stefansson, Kári Stefansson, Bernhard J. Steinhoff, Ulrich Stephani, William C. Stewart, Carlotta Stipa, Pasquale Striano, Hans Stroink, Adam Strzelczyk, Rainer Surges, Toshimitsu Suzuki, K. Meng Tan, R. S. Taneja, George A. Tanteles, Erik Taubøll, Liu Lin Thio, G. Neil Thomas, Rhys H. Thomas, Oskari Timonen, Paolo Tinuper, Marian Todaro, Pınar Topaloğlu, Rossana Tozzi, Meng-Han Tsai, Birute Tumiene, Dilsad Turkdogan, Unnur Unnsteinsdóttir, Algirdas Utkus, Priya Vaidiswaran, Luc Valton, Andreas van Baalen, Annalisa Vetro, Eileen P. G. Vining, Frank Visscher, Sophie von Brauchitsch, Randi von Wrede, Ryan G. Wagner, Yvonne G. Weber, Sarah Weckhuysen, Judith Weisenberg, Michael Weller, Peter Widdess-Walsh, Markus Wolff, Stefan Wolking, David Wu, Kazuhiro Yamakawa, Wanling Yang, Zuhal Yapıcı, Emrah Yücesan, Sara Zagaglia, Felix Zahnert, Federico Zara, Wei Zhou, Fritz Zimprich, Gábor Zsurka, Quratulain Zulfiqar Ali, Beata Fonferko-Shadrach, Owen Pickrell Orcid Logo

Nature Genetics, Volume: 55, Issue: 9, Pages: 1471 - 1482

Swansea University Authors: Mark Baker, Beata Fonferko-Shadrach, Owen Pickrell Orcid Logo

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DOI (Published version): 10.1038/s41588-023-01485-w

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 epileps...

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Published in: Nature Genetics
ISSN: 1061-4036 1546-1718
Published: Springer Science and Business Media LLC 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa67652
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2024-10-25T10:57:18.0663512</datestamp><bib-version>v2</bib-version><id>67652</id><entry>2024-09-11</entry><title>GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture</title><swanseaauthors><author><sid>89902d6839958558aa2cea1f8167035b</sid><firstname>Mark</firstname><surname>Baker</surname><name>Mark Baker</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>7d3f1e80939f2b8fab6a16b5ec6ac845</sid><firstname>Beata</firstname><surname>Fonferko-Shadrach</surname><name>Beata Fonferko-Shadrach</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>1c3044b5ff7a6552ff5e8c9e3901c807</sid><ORCID>0000-0003-4396-5657</ORCID><firstname>Owen</firstname><surname>Pickrell</surname><name>Owen Pickrell</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2024-09-11</date><abstract>Epilepsy is a highly heritable disorder affecting over 50&#x2009;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.</abstract><type>Journal Article</type><journal>Nature Genetics</journal><volume>55</volume><journalNumber>9</journalNumber><paginationStart>1471</paginationStart><paginationEnd>1482</paginationEnd><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1061-4036</issnPrint><issnElectronic>1546-1718</issnElectronic><keywords/><publishedDay>1</publishedDay><publishedMonth>9</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-09-01</publishedDate><doi>10.1038/s41588-023-01485-w</doi><url/><notes/><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>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&#x2019;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 &#x2018;Vrienden WKZ&#x2019; 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&#xE7;&#xE3;o de Amparo &#xE0; Pesquisa do Estado de S&#xE3;o Paulo (FAPESP), Brazil (grant 2013/07559-3) supported I.L.-C.</funders><projectreference/><lastEdited>2024-10-25T10:57:18.0663512</lastEdited><Created>2024-09-11T12:18:39.3576914</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>(International League Against Epilepsy Consortium on Complex</firstname><surname>Epilepsies)</surname><order>1</order></author><author><firstname>Remi</firstname><surname>Stevelink</surname><order>2</order></author><author><firstname>Ciar&#xE1;n</firstname><surname>Campbell</surname><order>3</order></author><author><firstname>Siwei</firstname><surname>Chen</surname><order>4</order></author><author><firstname>Bassel</firstname><surname>Abou-Khalil</surname><order>5</order></author><author><firstname>Oluyomi M.</firstname><surname>Adesoji</surname><order>6</order></author><author><firstname>Zaid</firstname><surname>Afawi</surname><order>7</order></author><author><firstname>Elisabetta</firstname><surname>Amadori</surname><order>8</order></author><author><firstname>Alison</firstname><surname>Anderson</surname><order>9</order></author><author><firstname>Joseph</firstname><surname>Anderson</surname><order>10</order></author><author><firstname>Danielle M.</firstname><surname>Andrade</surname><order>11</order></author><author><firstname>Grazia</firstname><surname>Annesi</surname><order>12</order></author><author><firstname>Pauls</firstname><surname>Auce</surname><order>13</order></author><author><firstname>Andreja</firstname><surname>Avbersek</surname><order>14</order></author><author><firstname>Melanie</firstname><surname>Bahlo</surname><order>15</order></author><author><firstname>Mark</firstname><surname>Baker</surname><order>16</order></author><author><firstname>Ganna</firstname><surname>Balagura</surname><order>17</order></author><author><firstname>Simona</firstname><surname>Balestrini</surname><order>18</order></author><author><firstname>Carmen</firstname><surname>Barba</surname><order>19</order></author><author><firstname>Karen</firstname><surname>Barboza</surname><order>20</order></author><author><firstname>Fabrice</firstname><surname>Bartolomei</surname><order>21</order></author><author><firstname>Thomas</firstname><surname>Bast</surname><order>22</order></author><author><firstname>Larry</firstname><surname>Baum</surname><order>23</order></author><author><firstname>Tobias</firstname><surname>Baumgartner</surname><order>24</order></author><author><firstname>Bet&#xFC;l</firstname><surname>Baykan</surname><order>25</order></author><author><firstname>Nerses</firstname><surname>Bebek</surname><order>26</order></author><author><firstname>Albert J.</firstname><surname>Becker</surname><order>27</order></author><author><firstname>Felicitas</firstname><surname>Becker</surname><order>28</order></author><author><firstname>Caitlin A.</firstname><surname>Bennett</surname><order>29</order></author><author><firstname>Bianca</firstname><surname>Berghuis</surname><order>30</order></author><author><firstname>Samuel F.</firstname><surname>Berkovic</surname><order>31</order></author><author><firstname>Ahmad</firstname><surname>Beydoun</surname><order>32</order></author><author><firstname>Claudia</firstname><surname>Bianchini</surname><order>33</order></author><author><firstname>Francesca</firstname><surname>Bisulli</surname><order>34</order></author><author><firstname>Ilan</firstname><surname>Blatt</surname><order>35</order></author><author><firstname>Dheeraj 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spelling 2024-10-25T10:57:18.0663512 v2 67652 2024-09-11 GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture 89902d6839958558aa2cea1f8167035b Mark Baker Mark Baker true false 7d3f1e80939f2b8fab6a16b5ec6ac845 Beata Fonferko-Shadrach Beata Fonferko-Shadrach true false 1c3044b5ff7a6552ff5e8c9e3901c807 0000-0003-4396-5657 Owen Pickrell Owen Pickrell true false 2024-09-11 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. Journal Article Nature Genetics 55 9 1471 1482 Springer Science and Business Media LLC 1061-4036 1546-1718 1 9 2023 2023-09-01 10.1038/s41588-023-01485-w COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee 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. 2024-10-25T10:57:18.0663512 2024-09-11T12:18:39.3576914 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine (International League Against Epilepsy Consortium on Complex Epilepsies) 1 Remi Stevelink 2 Ciarán Campbell 3 Siwei Chen 4 Bassel Abou-Khalil 5 Oluyomi M. Adesoji 6 Zaid Afawi 7 Elisabetta Amadori 8 Alison Anderson 9 Joseph Anderson 10 Danielle M. Andrade 11 Grazia Annesi 12 Pauls Auce 13 Andreja Avbersek 14 Melanie Bahlo 15 Mark Baker 16 Ganna Balagura 17 Simona Balestrini 18 Carmen Barba 19 Karen Barboza 20 Fabrice Bartolomei 21 Thomas Bast 22 Larry Baum 23 Tobias Baumgartner 24 Betül Baykan 25 Nerses Bebek 26 Albert J. Becker 27 Felicitas Becker 28 Caitlin A. Bennett 29 Bianca Berghuis 30 Samuel F. Berkovic 31 Ahmad Beydoun 32 Claudia Bianchini 33 Francesca Bisulli 34 Ilan Blatt 35 Dheeraj R. Bobbili 36 Ingo Borggraefe 37 Christian Bosselmann 38 Vera Braatz 39 Jonathan P. Bradfield 40 Knut Brockmann 41 Lawrence C. Brody 42 Russell J. Buono 43 Robyn M. Busch 44 Hande Caglayan 45 Ellen Campbell 46 Laura Canafoglia 47 Christina Canavati 48 Gregory D. Cascino 49 Barbara Castellotti 50 Claudia B. Catarino 51 Gianpiero L. Cavalleri 52 Felecia Cerrato 53 Francine Chassoux 54 Stacey S. Cherny 55 Ching-Lung Cheung 56 Krishna Chinthapalli 57 I-Jun Chou 58 Seo-Kyung Chung 59 Claire Churchhouse 60 Peggy O. Clark 61 Andrew J. Cole 62 Alastair Compston 63 Antonietta Coppola 64 Mahgenn Cosico 65 Patrick Cossette 66 John J. Craig 67 Caroline Cusick 68 Mark J. Daly 69 Lea K. Davis 70 Gerrit-Jan de Haan 71 Norman Delanty 72 Chantal Depondt 73 Philippe Derambure 74 Orrin Devinsky 75 Lidia Di Vito 76 Dennis J. Dlugos 77 Viola Doccini 78 Colin P. Doherty 79 Hany El-Naggar 80 Christian E. Elger 81 Colin A. Ellis 82 Johan G. Eriksson 83 Annika Faucon 84 Yen-Chen A. Feng 85 Lisa Ferguson 86 Thomas N. Ferraro 87 Lorenzo Ferri 88 Martha Feucht 89 Mark Fitzgerald 90 Beata Fonferko-Shadrach 91 Francesco Fortunato 92 Silvana Franceschetti 93 Andre Franke 94 Jacqueline A. French 95 Elena Freri 96 Monica Gagliardi 97 Antonio Gambardella 98 Eric B. Geller 99 Tania Giangregorio 100 Leif Gjerstad 101 Tracy Glauser 102 Ethan Goldberg 103 Alicia Goldman 104 Tiziana Granata 105 David A. Greenberg 106 Renzo Guerrini 107 Namrata Gupta 108 Kevin F. Haas 109 Hakon Hakonarson 110 Kerstin Hallmann 111 Emadeldin Hassanin 112 Manu Hegde 113 Erin L. Heinzen 114 Ingo Helbig 115 Christian Hengsbach 116 Henrike O. Heyne 117 Shinichi Hirose 118 Edouard Hirsch 119 Helle Hjalgrim 120 Daniel P. Howrigan 121 Donald Hucks 122 Po-Cheng Hung 123 Michele Iacomino 124 Lukas L. Imbach 125 Yushi Inoue 126 Atsushi Ishii 127 Jennifer Jamnadas-Khoda 128 Lara Jehi 129 Michael R. Johnson 130 Reetta Kälviäinen 131 Yoichiro Kamatani 132 Moien Kanaan 133 Masahiro Kanai 134 Anne-Mari Kantanen 135 Bülent Kara 136 Symon M. Kariuki 137 Dalia Kasperavičiūte 138 Dorothee Kasteleijn-Nolst Trenite 139 Mitsuhiro Kato 140 Josua Kegele 141 Yeşim Kesim 142 Nathalie Khoueiry-Zgheib 143 Chontelle King 144 Heidi E. Kirsch 145 Karl M. Klein 146 Gerhard Kluger 147 Susanne Knake 148 Robert C. Knowlton 149 Bobby P. C. Koeleman 150 Amos D. Korczyn 151 Andreas Koupparis 152 Ioanna Kousiappa 153 Roland Krause 154 Martin Krenn 155 Heinz Krestel 156 Ilona Krey 157 Wolfram S. Kunz 158 Mitja I. Kurki 159 Gerhard Kurlemann 160 Ruben Kuzniecky 161 Patrick Kwan 162 Angelo Labate 163 Austin Lacey 164 Dennis Lal 165 Zied Landoulsi 166 Yu-Lung Lau 167 Stephen Lauxmann 168 Stephanie L. Leech 169 Anna-Elina Lehesjoki 170 Johannes R. Lemke 171 Holger Lerche 172 Gaetan Lesca 173 Costin Leu 174 Naomi Lewin 175 David Lewis-Smith 176 Gloria H.-Y. Li 177 Qingqin S. Li 178 Laura Licchetta 179 Kuang-Lin Lin 180 Dick Lindhout 181 Tarja Linnankivi 182 Iscia Lopes-Cendes 183 Daniel H. Lowenstein 184 Colin H. T. Lui 185 Francesca Madia 186 Sigurdur Magnusson 187 Anthony G. Marson 188 Patrick May 189 Christopher M. McGraw 190 Davide Mei 191 James L. Mills 192 Raffaella Minardi 193 Nasir Mirza 194 Rikke S. Møller 195 Anne M. Molloy 196 Martino Montomoli 197 Barbara Mostacci 198 Lorenzo Muccioli 199 Hiltrud Muhle 200 Karen Müller-Schlüter 201 Imad M. Najm 202 Wassim Nasreddine 203 Benjamin M. Neale 204 Bernd Neubauer 205 Charles R. J. C. Newton 206 Markus M. Nöthen 207 Michael Nothnagel 208 Peter Nürnberg 209 Terence J. O’Brien 210 Yukinori Okada 211 Elías Ólafsson 212 Karen L. Oliver 213 Çiğdem Özkara 214 Aarno Palotie 215 Faith Pangilinan 216 Savvas S. Papacostas 217 Elena Parrini 218 Carlos N. Pato 219 Michele T. Pato 220 Manuela Pendziwiat 221 Slavé Petrovski 222 William O. Pickrell 223 Rebecca Pinsky 224 Tommaso Pippucci 225 Annapurna Poduri 226 Federica Pondrelli 227 Rob H. W. Powell 228 Michael Privitera 229 Annika Rademacher 230 Rodney Radtke 231 Francesca Ragona 232 Sarah Rau 233 Mark I. Rees 234 Brigid M. Regan 235 Philipp S. Reif 236 Sylvain Rhelms 237 Antonella Riva 238 Felix Rosenow 239 Philippe Ryvlin 240 Anni Saarela 241 Lynette G. Sadleir 242 Josemir W. Sander 243 Thomas Sander 244 Marcello Scala 245 Theresa Scattergood 246 Steven C. Schachter 247 Christoph J. Schankin 248 Ingrid E. Scheffer 249 Bettina Schmitz 250 Susanne Schoch 251 Susanne Schubert-Bast 252 Andreas Schulze-Bonhage 253 Paolo Scudieri 254 Pak Sham 255 Beth R. Sheidley 256 Jerry J. Shih 257 Graeme J. Sills 258 Sanjay M. Sisodiya 259 Michael C. Smith 260 Philip E. Smith 261 Anja C. M. Sonsma 262 Doug Speed 263 Michael R. Sperling 264 Hreinn Stefansson 265 Kári Stefansson 266 Bernhard J. Steinhoff 267 Ulrich Stephani 268 William C. Stewart 269 Carlotta Stipa 270 Pasquale Striano 271 Hans Stroink 272 Adam Strzelczyk 273 Rainer Surges 274 Toshimitsu Suzuki 275 K. Meng Tan 276 R. S. Taneja 277 George A. Tanteles 278 Erik Taubøll 279 Liu Lin Thio 280 G. Neil Thomas 281 Rhys H. Thomas 282 Oskari Timonen 283 Paolo Tinuper 284 Marian Todaro 285 Pınar Topaloğlu 286 Rossana Tozzi 287 Meng-Han Tsai 288 Birute Tumiene 289 Dilsad Turkdogan 290 Unnur Unnsteinsdóttir 291 Algirdas Utkus 292 Priya Vaidiswaran 293 Luc Valton 294 Andreas van Baalen 295 Annalisa Vetro 296 Eileen P. G. Vining 297 Frank Visscher 298 Sophie von Brauchitsch 299 Randi von Wrede 300 Ryan G. Wagner 301 Yvonne G. Weber 302 Sarah Weckhuysen 303 Judith Weisenberg 304 Michael Weller 305 Peter Widdess-Walsh 306 Markus Wolff 307 Stefan Wolking 308 David Wu 309 Kazuhiro Yamakawa 310 Wanling Yang 311 Zuhal Yapıcı 312 Emrah Yücesan 313 Sara Zagaglia 314 Felix Zahnert 315 Federico Zara 316 Wei Zhou 317 Fritz Zimprich 318 Gábor Zsurka 319 Quratulain Zulfiqar Ali 320 Beata Fonferko-Shadrach 321 Owen Pickrell 0000-0003-4396-5657 322 67652__32713__61c14495563e42a49f47f64f83aee6dd.pdf 67652.VoR.pdf 2024-10-25T10:55:59.9981264 Output 2934446 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
spellingShingle GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Mark Baker
Beata Fonferko-Shadrach
Owen Pickrell
title_short GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
title_full GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
title_fullStr GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
title_full_unstemmed GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
title_sort GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
author_id_str_mv 89902d6839958558aa2cea1f8167035b
7d3f1e80939f2b8fab6a16b5ec6ac845
1c3044b5ff7a6552ff5e8c9e3901c807
author_id_fullname_str_mv 89902d6839958558aa2cea1f8167035b_***_Mark Baker
7d3f1e80939f2b8fab6a16b5ec6ac845_***_Beata Fonferko-Shadrach
1c3044b5ff7a6552ff5e8c9e3901c807_***_Owen Pickrell
author Mark Baker
Beata Fonferko-Shadrach
Owen Pickrell
author2 (International League Against Epilepsy Consortium on Complex Epilepsies)
Remi Stevelink
Ciarán Campbell
Siwei Chen
Bassel Abou-Khalil
Oluyomi M. Adesoji
Zaid Afawi
Elisabetta Amadori
Alison Anderson
Joseph Anderson
Danielle M. Andrade
Grazia Annesi
Pauls Auce
Andreja Avbersek
Melanie Bahlo
Mark Baker
Ganna Balagura
Simona Balestrini
Carmen Barba
Karen Barboza
Fabrice Bartolomei
Thomas Bast
Larry Baum
Tobias Baumgartner
Betül Baykan
Nerses Bebek
Albert J. Becker
Felicitas Becker
Caitlin A. Bennett
Bianca Berghuis
Samuel F. Berkovic
Ahmad Beydoun
Claudia Bianchini
Francesca Bisulli
Ilan Blatt
Dheeraj R. Bobbili
Ingo Borggraefe
Christian Bosselmann
Vera Braatz
Jonathan P. Bradfield
Knut Brockmann
Lawrence C. Brody
Russell J. Buono
Robyn M. Busch
Hande Caglayan
Ellen Campbell
Laura Canafoglia
Christina Canavati
Gregory D. Cascino
Barbara Castellotti
Claudia B. Catarino
Gianpiero L. Cavalleri
Felecia Cerrato
Francine Chassoux
Stacey S. Cherny
Ching-Lung Cheung
Krishna Chinthapalli
I-Jun Chou
Seo-Kyung Chung
Claire Churchhouse
Peggy O. Clark
Andrew J. Cole
Alastair Compston
Antonietta Coppola
Mahgenn Cosico
Patrick Cossette
John J. Craig
Caroline Cusick
Mark J. Daly
Lea K. Davis
Gerrit-Jan de Haan
Norman Delanty
Chantal Depondt
Philippe Derambure
Orrin Devinsky
Lidia Di Vito
Dennis J. Dlugos
Viola Doccini
Colin P. Doherty
Hany El-Naggar
Christian E. Elger
Colin A. Ellis
Johan G. Eriksson
Annika Faucon
Yen-Chen A. Feng
Lisa Ferguson
Thomas N. Ferraro
Lorenzo Ferri
Martha Feucht
Mark Fitzgerald
Beata Fonferko-Shadrach
Francesco Fortunato
Silvana Franceschetti
Andre Franke
Jacqueline A. French
Elena Freri
Monica Gagliardi
Antonio Gambardella
Eric B. Geller
Tania Giangregorio
Leif Gjerstad
Tracy Glauser
Ethan Goldberg
Alicia Goldman
Tiziana Granata
David A. Greenberg
Renzo Guerrini
Namrata Gupta
Kevin F. Haas
Hakon Hakonarson
Kerstin Hallmann
Emadeldin Hassanin
Manu Hegde
Erin L. Heinzen
Ingo Helbig
Christian Hengsbach
Henrike O. Heyne
Shinichi Hirose
Edouard Hirsch
Helle Hjalgrim
Daniel P. Howrigan
Donald Hucks
Po-Cheng Hung
Michele Iacomino
Lukas L. Imbach
Yushi Inoue
Atsushi Ishii
Jennifer Jamnadas-Khoda
Lara Jehi
Michael R. Johnson
Reetta Kälviäinen
Yoichiro Kamatani
Moien Kanaan
Masahiro Kanai
Anne-Mari Kantanen
Bülent Kara
Symon M. Kariuki
Dalia Kasperavičiūte
Dorothee Kasteleijn-Nolst Trenite
Mitsuhiro Kato
Josua Kegele
Yeşim Kesim
Nathalie Khoueiry-Zgheib
Chontelle King
Heidi E. Kirsch
Karl M. Klein
Gerhard Kluger
Susanne Knake
Robert C. Knowlton
Bobby P. C. Koeleman
Amos D. Korczyn
Andreas Koupparis
Ioanna Kousiappa
Roland Krause
Martin Krenn
Heinz Krestel
Ilona Krey
Wolfram S. Kunz
Mitja I. Kurki
Gerhard Kurlemann
Ruben Kuzniecky
Patrick Kwan
Angelo Labate
Austin Lacey
Dennis Lal
Zied Landoulsi
Yu-Lung Lau
Stephen Lauxmann
Stephanie L. Leech
Anna-Elina Lehesjoki
Johannes R. Lemke
Holger Lerche
Gaetan Lesca
Costin Leu
Naomi Lewin
David Lewis-Smith
Gloria H.-Y. Li
Qingqin S. Li
Laura Licchetta
Kuang-Lin Lin
Dick Lindhout
Tarja Linnankivi
Iscia Lopes-Cendes
Daniel H. Lowenstein
Colin H. T. Lui
Francesca Madia
Sigurdur Magnusson
Anthony G. Marson
Patrick May
Christopher M. McGraw
Davide Mei
James L. Mills
Raffaella Minardi
Nasir Mirza
Rikke S. Møller
Anne M. Molloy
Martino Montomoli
Barbara Mostacci
Lorenzo Muccioli
Hiltrud Muhle
Karen Müller-Schlüter
Imad M. Najm
Wassim Nasreddine
Benjamin M. Neale
Bernd Neubauer
Charles R. J. C. Newton
Markus M. Nöthen
Michael Nothnagel
Peter Nürnberg
Terence J. O’Brien
Yukinori Okada
Elías Ólafsson
Karen L. Oliver
Çiğdem Özkara
Aarno Palotie
Faith Pangilinan
Savvas S. Papacostas
Elena Parrini
Carlos N. Pato
Michele T. Pato
Manuela Pendziwiat
Slavé Petrovski
William O. Pickrell
Rebecca Pinsky
Tommaso Pippucci
Annapurna Poduri
Federica Pondrelli
Rob H. W. Powell
Michael Privitera
Annika Rademacher
Rodney Radtke
Francesca Ragona
Sarah Rau
Mark I. Rees
Brigid M. Regan
Philipp S. Reif
Sylvain Rhelms
Antonella Riva
Felix Rosenow
Philippe Ryvlin
Anni Saarela
Lynette G. Sadleir
Josemir W. Sander
Thomas Sander
Marcello Scala
Theresa Scattergood
Steven C. Schachter
Christoph J. Schankin
Ingrid E. Scheffer
Bettina Schmitz
Susanne Schoch
Susanne Schubert-Bast
Andreas Schulze-Bonhage
Paolo Scudieri
Pak Sham
Beth R. Sheidley
Jerry J. Shih
Graeme J. Sills
Sanjay M. Sisodiya
Michael C. Smith
Philip E. Smith
Anja C. M. Sonsma
Doug Speed
Michael R. Sperling
Hreinn Stefansson
Kári Stefansson
Bernhard J. Steinhoff
Ulrich Stephani
William C. Stewart
Carlotta Stipa
Pasquale Striano
Hans Stroink
Adam Strzelczyk
Rainer Surges
Toshimitsu Suzuki
K. Meng Tan
R. S. Taneja
George A. Tanteles
Erik Taubøll
Liu Lin Thio
G. Neil Thomas
Rhys H. Thomas
Oskari Timonen
Paolo Tinuper
Marian Todaro
Pınar Topaloğlu
Rossana Tozzi
Meng-Han Tsai
Birute Tumiene
Dilsad Turkdogan
Unnur Unnsteinsdóttir
Algirdas Utkus
Priya Vaidiswaran
Luc Valton
Andreas van Baalen
Annalisa Vetro
Eileen P. G. Vining
Frank Visscher
Sophie von Brauchitsch
Randi von Wrede
Ryan G. Wagner
Yvonne G. Weber
Sarah Weckhuysen
Judith Weisenberg
Michael Weller
Peter Widdess-Walsh
Markus Wolff
Stefan Wolking
David Wu
Kazuhiro Yamakawa
Wanling Yang
Zuhal Yapıcı
Emrah Yücesan
Sara Zagaglia
Felix Zahnert
Federico Zara
Wei Zhou
Fritz Zimprich
Gábor Zsurka
Quratulain Zulfiqar Ali
Beata Fonferko-Shadrach
Owen Pickrell
format Journal article
container_title Nature Genetics
container_volume 55
container_issue 9
container_start_page 1471
publishDate 2023
institution Swansea University
issn 1061-4036
1546-1718
doi_str_mv 10.1038/s41588-023-01485-w
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
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.
published_date 2023-09-01T18:44:42Z
_version_ 1831847049856811008
score 11.058631

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