GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Authors:   International League Against Epilepsy Consortium on Complex Epilepsies, Stevelink Remi , Campbell Ciarán , Chen Siwei , Abou-Khalil Bassel , Adesoji Oluyomi M. , Afawi Zaid , Amadori Elisabetta , Anderson Alison , Anderson Joseph , Andrade Danielle M. , Annesi Grazia , Auce Pauls , Avbersek Andreja , Bahlo Melanie , Baker Mark D. , Balagura Ganna , Balestrini Simona , Barba Carmen , Barboza Karen , Bartolomei Fabrice , Bast Thomas , Baum Larry , Baumgartner Tobias , Baykan Betül , Bebek Nerses , Becker Albert J. , Becker Felicitas , Bennett Caitlin A. , Berghuis Bianca , Berkovic Samuel F. , Beydoun Ahmad , Bianchini Claudia , Bisulli Francesca , Blatt Ilan , Bobbili Dheeraj R. , Borggraefe Ingo , Bosselmann Christian , Braatz Vera , Bradfield Jonathan P. , Brockmann Knut , Brody Lawrence C. , Buono Russell J. , Busch Robyn M. , Caglayan Hande , Campbell Ellen , Canafoglia Laura , Canavati Christina , Cascino Gregory D. , Castellotti Barbara , Catarino Claudia B. , Cavalleri Gianpiero L. , Cerrato Felecia , Chassoux Francine , Cherny Stacey S. , Cheung Ching-Lung , Chinthapalli Krishna , Chou I-Jun , Chung Seo-Kyung , Churchhouse Claire , Clark Peggy O. , Cole Andrew J. , Compston Alastair , Coppola Antonietta , Cosico Mahgenn , Cossette Patrick , Craig John J. , Cusick Caroline , Daly Mark J. , Davis Lea K. , de Haan Gerrit-Jan , Delanty Norman , Depondt Chantal , Derambure Philippe , Devinsky Orrin , Di Vito Lidia , Dlugos Dennis J. , Doccini Viola , Doherty Colin P. , El-Naggar Hany , Elger Christian E. , Ellis Colin A. , Eriksson Johan G. , Faucon Annika , Feng Yen-Chen A. , Ferguson Lisa , Ferraro Thomas N. , Ferri Lorenzo , Feucht Martha , Fitzgerald Mark , Fonferko-Shadrach Beata , Fortunato Francesco , Franceschetti Silvana , Franke Andre , French Jacqueline A. , Freri Elena , Gagliardi Monica , Gambardella Antonio , Geller Eric B. , Giangregorio Tania , Gjerstad Leif , Glauser Tracy , Goldberg Ethan , Goldman Alicia , Granata Tiziana , Greenberg David A. , Guerrini Renzo , Gupta Namrata , Haas Kevin F. , Hakonarson Hakon , Hallmann Kerstin , Hassanin Emadeldin , Hegde Manu , Heinzen Erin L. , Helbig Ingo , Hengsbach Christian , Heyne Henrike O. , Hirose Shinichi , Hirsch Edouard , Hjalgrim Helle , Howrigan Daniel P. , Hucks Donald , Hung Po-Cheng , Iacomino Michele , Imbach Lukas L. , Inoue Yushi , Ishii Atsushi , Jamnadas-Khoda Jennifer , Jehi Lara , Johnson Michael R. , Kälviäinen Reetta , Kamatani Yoichiro , Kanaan Moien , Kanai Masahiro , Kantanen Anne-Mari , Kara Bülent , Kariuki Symon M. , Kasperavičiūte Dalia , Kasteleijn-Nolst Trenite Dorothee , Kato Mitsuhiro , Kegele Josua , Kesim Yeşim , Khoueiry-Zgheib Nathalie , King Chontelle , Kirsch Heidi E. , Klein Karl M. , Kluger Gerhard , Knake Susanne , Knowlton Robert C. , Koeleman Bobby P. C. , Korczyn Amos D. , Koupparis Andreas , Kousiappa Ioanna , Krause Roland , Krenn Martin , Krestel Heinz , Krey Ilona , Kunz Wolfram S. , Kurki Mitja I. , Kurlemann Gerhard , Kuzniecky Ruben , Kwan Patrick , Labate Angelo , Lacey Austin , Lal Dennis , Landoulsi Zied , Lau Yu-Lung , Lauxmann Stephen , Leech Stephanie L. , Lehesjoki Anna-Elina , Lemke Johannes R. , Lerche Holger , Lesca Gaetan , Leu Costin , Lewin Naomi , Lewis-Smith David , Li Gloria H.-Y. , Li Qingqin S. , Licchetta Laura , Lin Kuang-Lin , Lindhout Dick , Linnankivi Tarja , Lopes-Cendes Iscia , Lowenstein Daniel H. , Lui Colin H. T. , Madia Francesca , Magnusson Sigurdur , Marson Anthony G. , May Patrick , McGraw Christopher M. , Mei Davide , Mills James L. , Minardi Raffaella , Mirza Nasir , Møller Rikke S. , Molloy Anne M. , Montomoli Martino , Mostacci Barbara , Muccioli Lorenzo , Muhle Hiltrud , Müller-Schlüter Karen , Najm Imad M. , Nasreddine Wassim , Neale Benjamin M. , Neubauer Bernd , Newton Charles R. J. C. , Nöthen Markus M. , Nothnagel Michael , Nürnberg Peter , O’Brien Terence J. , Okada Yukinori , Ólafsson Elías , Oliver Karen L. , Özkara Çiğdem , Palotie Aarno , Pangilinan Faith , Papacostas Savvas S. , Parrini Elena , Pato Carlos N. , Pato Michele T. , Pendziwiat Manuela , Petrovski Slavé , Pickrell William O. , Pinsky Rebecca , Pippucci Tommaso , Poduri Annapurna , Pondrelli Federica , Powell Rob H. W. , Privitera Michael , Rademacher Annika , Radtke Rodney , Ragona Francesca , Rau Sarah , Rees Mark I. , Regan Brigid M. , Reif Philipp S. , Rhelms Sylvain , Riva Antonella , Rosenow Felix , Ryvlin Philippe , Saarela Anni , Sadleir Lynette G. , Sander Josemir W. , Sander Thomas , Scala Marcello , Scattergood Theresa , Schachter Steven C. , Schankin Christoph J. , Scheffer Ingrid E. , Schmitz Bettina , Schoch Susanne , Schubert-Bast Susanne , Schulze-Bonhage Andreas , Scudieri Paolo , Sham Pak , Sheidley Beth R. , Shih Jerry J. , Sills Graeme J. , Sisodiya Sanjay M. , Smith Michael C. , Smith Philip E. , Sonsma Anja C. M. , Speed Doug , Sperling Michael R. , Stefansson Hreinn , Stefansson Kári , Steinhoff Bernhard J. , Stephani Ulrich , Stewart William C. , Stipa Carlotta , Striano Pasquale , Stroink Hans , Strzelczyk Adam , Surges Rainer , Suzuki Toshimitsu , Tan K. Meng , Taneja R. S. , Tanteles George A. , Taubøll Erik , Thio Liu Lin , Thomas G. Neil , Thomas Rhys H. , Timonen Oskari , Tinuper Paolo , Todaro Marian , Topaloğlu Pınar , Tozzi Rossana , Tsai Meng-Han , Tumiene Birute , Turkdogan Dilsad , Unnsteinsdóttir Unnur , Utkus Algirdas , Vaidiswaran Priya , Valton Luc , van Baalen Andreas , Vetro Annalisa , Vining Eileen P. G. , Visscher Frank , von Brauchitsch Sophie , von Wrede Randi , Wagner Ryan G. , Weber Yvonne G. , Weckhuysen Sarah , Weisenberg Judith , Weller Michael , Widdess-Walsh Peter , Wolff Markus , Wolking Stefan , Wu David , Yamakawa Kazuhiro , Yang Wanling , Yapıcı Zuhal , Yücesan Emrah , Zagaglia Sara , Zahnert Felix , Zara Federico , Zhou Wei , Zimprich Fritz , Zsurka Gábor , Zulfiqar Ali Quratulain 
Published: August 2023

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.