GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Authors: 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 Avberšek, Melanie Bahlo, Mark D. Baker, Ganna Balagura, Simona Balestrini, Carmen Barba, Karen Barboza, Fabrice Bartoloméi, 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 Reddy Bobbili, Ingo Borggraefe, Christian M. Boßelmann, Vera Braatz, Jonathan P. Bradfield, Knut Brockmann, Lawrence C. Brody, Russell J. Buono, Robyn M. Busch, Hande Çağlayan, 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 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 Dlugos, Viola Doccini, Colin P. Doherty, Hany El-Naggar, Christian E. Elger, Colin A. Ellis, Johan G. Eriksson, Annika Faucon, Yen‐Chen Anne Feng, Lisa Ferguson, Thomas N. Ferraro, Lorenzo Ferri, Martha Feucht, Mark P. 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 A. Glauser, Ethan M. Goldberg, Alicia Goldman, Tiziana Granata, David A. Greenberg, Renzo Guerrini, Namrata Gupta, Kevin F. Haas, Håkon Håkonarson, Kerstin Hallmann, Emadeldin Hassanin, Manu Hegde, Erin L. Heinzen, Ingo Helbig, Christian Hengsbach, Henrike Heyne, Shinichi Hirose, Édouard Hirsch, Helle Hjalgrim, Daniel P. Howrigan, Donald Hucks, Po‐Cheng Hung, Michele Iacomino, Lukas 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 Kasperavičiūtė, Dorothée Kasteleijn‐Nolst Trenité, Mitsuhiro Kato, Josua Kegele, Yeşim Kesim, Nathalie K. Zgheib, Chontelle King, Heidi E. Kirsch, Karl Martin 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 Kurki, Gerhard Kurlemann, Ruben Kuzniecky, Patrick Kwan, Angelo Labate, Austin Lacey, Dennis Lal, Zied Landoulsi, YL Lau, Stephen Lauxmann, Stephanie L. Leech, Anna‐Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Gaëtan Lesca, Costin Leu, Naomi Lewin, David Lewis‐Smith, Gloria Hoi‐Yee Li, Qingqin S. Li, Laura Licchetta, Kuang-Lin Lin, Dick Lindhout, Tarja Linnankivi, Íscia Lopes‐Cendes, Daniel H. Lowenstein, Colin H. T. Lui, Francesca Madia, Sigurður H. Magnússon, 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 Najm, Wassim Nasreddine, Benjamin M. Neale, Bernd A. Neubauer, Charles R. Newton, Markus M. Nöthen, Michael Nothnagel, Peter Nürnberg, Terence J. O’Brien, Yukinori Okada, Elías Ólafsson, Karen Oliver, Çiğdem Özkara, Aarno Palotie, Faith Pangilinan, Savvas Papacostas, Elena Parrini, Carlos N. Pato, Michele T. Pato, Manuela Pendziwiat, Slavé Petrovski, William Owen Pickrell, Rebecca Pinsky, Tommaso Pippucci, Annapurna Poduri, Federica Pondrelli, Robert Powell, Michael Privitera, Annika Rademacher, Rodney A. 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 C. Sham, Beth Rosen Sheidley, Jerry J. Shih, Graeme J. Sills, Sanjay M. Sisodiya, Michael C. Smith, Phil E M Smith, Anja C. M. Sonsma, Doug Speed, Michael R. Sperling, Hreinn Stefánsson, 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. 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, Biruté Tumiene, Dilşad Türkdoğan, 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 Weber, Sarah Weckhuysen, Judith Weisenberg, Michael Weller, Peter Widdess‐Walsh, Markus Wolff, Stefan Wolking, David Wu, Kazuhiro Yamakawa, Wanling Yang, Zühal Yapıcı, Emrah Yücesan, Sara Zagaglia, Felix Zahnert, Federico Zara, Wei Zhou, Fritz Zimprich, Gábor Zsurka, Quratulain Zulfiqar Ali - Nature Genetics 2023 cited by 212

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.