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

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., Kasperavi'i'te, Dalia, Kasteleijn-Nolst Trenite, Dorothee, Kato, Mitsuhiro, Kegele, Josua, Kesim, Yes'im, 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, C'ig'dem, 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. ORCID: https://orcid.org/0000-0003-4250-2562, 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. ORCID: https://orcid.org/0000-0003-2062-8623, Timonen, Oskari, Tinuper, Paolo, Todaro, Marian, Topalo'lu, P'nar, 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, Yap'c', Zuhal, Yücesan, Emrah, Zagaglia, Sara, Zahnert, Felix, Zara, Federico, Zhou, Wei, Zimprich, Fritz, Zsurka, Gábor and Zulfiqar Ali, Quratulain 2023. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nature Genetics 55 (9) , pp. 1471-1482. 10.1038/s41588-023-01485-w

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	23 April 2024
Date of Acceptance:	21 July 2023
Last Modified:	03 Sep 2024 09:21
URI:	https://orca.cardiff.ac.uk/id/eprint/168241

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