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

Stevelink, R. et al. (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. (doi: 10.1038/s41588-023-01485-w) (PMID:37653029) (PMCID:PMC10484785)

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: Articles
• Additional Information: Authors from the International League Against Epilepsy Consortium on Complex Epilepsies. 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.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sills, Dr Graeme
• Authors: Stevelink, R., Campbell, C., Chen, S., Abou-Khalil, B., Adesoji, O. M., Afawi, Z., Amadori, E., Anderson, A., Anderson, J., Andrade, D. M., Annesi, G., Auce, P., Avbersek, A., Bahlo, M., Baker, M. D., Balagura, G., Balestrini, S., Barba, C., Barboza, K., Bartolomei, F., Bast, T., Baum, L., Baumgartner, T., Baykan, B., Bebek, N., Becker, A. J., Becker, F., Bennett, C. A., Berghuis, B., Berkovic, S. F., Beydoun, A., Bianchini, C., Bisulli, F., Blatt, I., Bobbili, D. R., Borggraefe, I., Bosselmann, C., Braatz, V., Bradfield, J. P., Brockmann, K., Brody, L. C., Buono, R. J., Busch, R. M., Caglayan, H., Campbell, E., Canafoglia, L., Canavati, C., Cascino, G. D., Castellotti, B., Catarino, C. B., Cavalleri, G. L., Cerrato, F., Chassoux, F., Cherny, S. S., Cheung, C.-L., Chinthapalli, K., Chou, I.-J., Chung, S.-K., Churchhouse, C., Clark, P. O., Cole, A. J., Compston, A., Coppola, A., Cosico, M., Cossette, P., Craig, J. J., Cusick, C., Daly, M. J., Davis, L. K., de Haan, G.-J., Delanty, N., Depondt, C., Derambure, P., Devinsky, O., Di Vito, L., Dlugos, D. J., Doccini, V., Doherty, C. P., El-Naggar, H., Elger, C. E., Ellis, C. A., Eriksson, J. G., Faucon, A., Feng, Y.-C. A., Ferguson, L., Ferraro, T. N., Ferri, L., Feucht, M., Fitzgerald, M., Fonferko-Shadrach, B., Fortunato, F., Franceschetti, S., Franke, A., French, J. A., Freri, E., Gagliardi, M., Gambardella, A., Geller, E. B., Giangregorio, T., Gjerstad, L., Glauser, T., Goldberg, E., Goldman, A., Granata, T., Greenberg, D. A., Guerrini, R., Gupta, N., Haas, K. F., Hakonarson, H., Hallmann, K., Hassanin, E., Hegde, M., Heinzen, E. L., Helbig, I., Hengsbach, C., Heyne, H. O., Hirose, S., Hirsch, E., Hjalgrim, H., Howrigan, D. P., Hucks, D., Hung, P.-C., Iacomino, M., Imbach, L. L., Inoue, Y., Ishii, A., Jamnadas-Khoda, J., Jehi, L., Johnson, M. R., Kälviäinen, R., Kamatani, Y., Kanaan, M., Kanai, M., Kantanen, A.-M., Kara, B., Kariuki, S. M., Kasperavičiūte, D., Kasteleijn-Nolst Trenite, D., Kato, M., Kegele, J., Kesim, Y., Khoueiry-Zgheib, N., King, C., Kirsch, H. E., Klein, K. M., Kluger, G., Knake, S., Knowlton, R. C., Koeleman, B. P. C., Korczyn, A. D., Koupparis, A., Kousiappa, I., Krause, R., Krenn, M., Krestel, H., Krey, I., Kunz, W. S., Kurki, M. I., Kurlemann, G., Kuzniecky, R., Kwan, P., Labate, A., Lacey, A., Lal, D., Landoulsi, Z., Lau, Y.-L., Lauxmann, S., Leech, S. L., Lehesjoki, A.-E., Lemke, J. R., Lerche, H., Lesca, G., Leu, C., Lewin, N., Lewis-Smith, D., Li, G. H.-Y., Li, Q. S., Licchetta, L., Lin, K.-L., Lindhout, D., Linnankivi, T., Lopes-Cendes, I., Lowenstein, D. H., Lui, C. H. T., Madia, F., Magnusson, S., Marson, A. G., May, P., McGraw, C. M., Mei, D., Mills, J. L., Minardi, R., Mirza, N., Møller, R. S., Molloy, A. M., Montomoli, M., Mostacci, B., Muccioli, L., Muhle, H., Müller-Schlüter, K., Najm, I. M., Nasreddine, W., Neale, B. M., Neubauer, B., Newton, C. R. J. C., Nöthen, M. M., Nothnagel, M., Nürnberg, P., O’Brien, T. J., Okada, Y., Ólafsson, E., Oliver, K. L., Özkara, C., Palotie, A., Pangilinan, F., Papacostas, S. S., Parrini, E., Pato, C. N., Pato, M. T., Pendziwiat, M., Petrovski, S., Pickrell, W. O., Pinsky, R., Pippucci, T., Poduri, A., Pondrelli, F., Powell, R. H. W., Privitera, M., Rademacher, A., Radtke, R., Ragona, F., Rau, S., Rees, M. I., Regan, B. M., Reif, P. S., Rhelms, S., Riva, A., Rosenow, F., Ryvlin, P., Saarela, A., Sadleir, L. G., Sander, J. W., Sander, T., Scala, M., Scattergood, T., Schachter, S. C., Schankin, C. J., Scheffer, I. E., Schmitz, B., Schoch, S., Schubert-Bast, S., Schulze-Bonhage, A., Scudieri, P., Sham, P., Sheidley, B. R., Shih, J. J., Sills, G. J., Sisodiya, S. M., Smith, M. C., Smith, P. E., Sonsma, A. C. M., Speed, D., Sperling, M. R., Stefansson, H., Stefansson, K., Steinhoff, B. J., Stephani, U., Stewart, W. C., Stipa, C., Striano, P., Stroink, H., Strzelczyk, A., Surges, R., Suzuki, T., Tan, K. M., Taneja, R. S., Tanteles, G. A., Taubøll, E., Thio, L. L., Thomas, G. N., Thomas, R. H., Timonen, O., Tinuper, P., Todaro, M., Topaloğlu, P., Tozzi, R., Tsai, M.-H., Tumiene, B., Turkdogan, D., Unnsteinsdóttir, U., Utkus, A., Vaidiswaran, P., Valton, L., van Baalen, A., Vetro, A., Vining, E. P. G., Visscher, F., von Brauchitsch, S., von Wrede, R., Wagner, R. G., Weber, Y. G., Weckhuysen, S., Weisenberg, J., Weller, M., Widdess-Walsh, P., Wolff, M., Wolking, S., Wu, D., Yamakawa, K., Yang, W., Yapıcı, Z., Yücesan, E., Zagaglia, S., Zahnert, F., Zara, F., Zhou, W., Zimprich, F., Zsurka, G., and Zulfiqar Ali, Q.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Genetics
• Publisher: Nature Research
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Published Online: 31 August 2023
• Copyright Holders: Copyright © 2023 The Author(s)
• First Published: First published in Nature Genetics 55(9):1471-1482
• Publisher Policy: Reproduced under a Creative Commons license