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