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Lookup NU author(s): Dr Rhys ThomasORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, The Author(s).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.
Author(s): Stevelink R, Campbell C, Chen S, Abou-Khalil B, Adesoji OM, Afawi Z, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Auce P, Avbersek A, Bahlo M, Baker MD, Balagura G, Balestrini S, Barba C, Barboza K, Bartolomei F, Bast T, Baum L, Baumgartner T, Baykan B, Bebek N, Becker AJ, Becker F, Bennett CA, Berghuis B, Berkovic SF, Beydoun A, Bianchini C, Bisulli F, Blatt I, Bobbili DR, Borggraefe I, Bosselmann C, Braatz V, Bradfield JP, Brockmann K, Brody LC, Buono RJ, Busch RM, Caglayan H, Campbell E, Canafoglia L, Canavati C, Cascino GD, Castellotti B, Catarino CB, Cavalleri GL, Cerrato F, Chassoux F, Cherny SS, Cheung C-L, Chinthapalli K, Chou I-J, Chung S-K, Churchhouse C, Clark PO, Cole AJ, Compston A, Coppola A, Cosico M, Cossette P, Craig JJ, Cusick C, Daly MJ, Davis LK, de Haan G-J, Delanty N, Depondt C, Derambure P, Devinsky O, Di Vito L, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Elger CE, Ellis CA, Eriksson JG, Faucon A, Feng Y-CA, Ferguson L, Ferraro TN, Ferri L, Feucht M, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, Franke A, French JA, Freri E, Gagliardi M, Gambardella A, Geller EB, Giangregorio T, Gjerstad L, Glauser T, Goldberg E, Goldman A, Granata T, Greenberg DA, Guerrini R, Gupta N, Haas KF, Hakonarson H, Hallmann K, Hassanin E, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne HO, Hirose S, Hirsch E, Hjalgrim H, Howrigan DP, Hucks D, Hung P-C, Iacomino M, Imbach LL, Inoue Y, Ishii A, Jamnadas-Khoda J, Jehi L, Johnson MR, Kalviainen R, Kamatani Y, Kanaan M, Kanai M, Kantanen A-M, Kara B, Kariuki SM, Kasperaviciute D, Kasteleijn-Nolst Trenite D, Kato M, Kegele J, Kesim Y, Khoueiry-Zgheib N, King C, Kirsch HE, Klein KM, Kluger G, Knake S, Knowlton RC, Koeleman BPC, Korczyn AD, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurki MI, Kurlemann G, Kuzniecky R, Kwan P, Labate A, Lacey A, Lal D, Landoulsi Z, Lau Y-L, Lauxmann S, Leech SL, Lehesjoki A-E, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH-Y, Li QS, Licchetta L, Lin K-L, Lindhout D, Linnankivi T, Lopes-Cendes I, Lowenstein DH, Lui CHT, Madia F, Magnusson S, Marson AG, May P, McGraw CM, Mei D, Mills JL, Minardi R, Mirza N, Moller RS, Molloy AM, Montomoli M, Mostacci B, Muccioli L, Muhle H, Muller-Schluter K, Najm IM, Nasreddine W, Neale BM, Neubauer B, Newton CRJC, Nothen MM, Nothnagel M, Nurnberg P, O'Brien TJ, Okada Y, Olafsson E, Oliver KL, Ozkara C, Palotie A, Pangilinan F, Papacostas SS, Parrini E, Pato CN, Pato MT, Pendziwiat M, Petrovski S, Pickrell WO, Pinsky R, Pippucci T, Poduri A, Pondrelli F, Powell RHW, Privitera M, Rademacher A, Radtke R, Ragona F, Rau S, Rees MI, Regan BM, Reif PS, Rhelms S, Riva A, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Sander JW, Sander T, Scala M, Scattergood T, Schachter SC, Schankin CJ, Scheffer IE, Schmitz B, Schoch S, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sham P, Sheidley BR, Shih JJ, Sills GJ, Sisodiya SM, Smith MC, Smith PE, Sonsma ACM, Speed D, Sperling MR, Stefansson H, Stefansson K, Steinhoff BJ, Stephani U, Stewart WC, Stipa C, Striano P, Stroink H, Strzelczyk A, Surges R, Suzuki T, Tan KM, Taneja RS, Tanteles GA, Tauboll E, Thio LL, Thomas GN, Thomas RH, Timonen O, Tinuper P, Todaro M, Topaloglu P, Tozzi R, Tsai M-H, Tumiene B, Turkdogan D, Unnsteinsdottir U, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vetro A, Vining EPG, Visscher F, von Brauchitsch S, von Wrede R, Wagner RG, Weber YG, Weckhuysen S, Weisenberg J, Weller M, Widdess-Walsh P, Wolff M, Wolking S, Wu D, Yamakawa K, Yang W, Yapici Z, Yucesan E, Zagaglia S, Zahnert F, Zara F, Zhou W, Zimprich F, Zsurka G, Zulfiqar Ali Q
Publication type: Article
Publication status: Published
Journal: Nature Genetics
Year: 2023
Volume: 55
Pages: 1471–1482
Print publication date: 01/09/2023
Online publication date: 31/08/2023
Acceptance date: 21/07/2023
Date deposited: 05/10/2023
ISSN (print): 1061-4036
ISSN (electronic): 1546-1718
Publisher: Nature Research
URL: https://doi.org/10.1038/s41588-023-01485-w
DOI: 10.1038/s41588-023-01485-w
Data Access Statement: The GWAS summary statistics data that support the findings of this study (for both multi-ancestry and European-only analyses) are publicly available at https://www.epigad.org/ and in the NHGRI-EBI GWAS Catalog at https://www.ebi.ac.uk/gwas/ (accession IDs: GCST90271608, GCST90271609, GCST90271610, GCST90271611, GCST90271612, GCST90271613, GCST90271614, GCST90271615, GCST90271616, GCST90271617, GCST90271618, GCST90271619 and GCST90271620). Remainder of data availability statement at https://doi.org/10.1038/s41588-023-01485-w
PubMed id: 37653029
Notes: International League Against Epilepsy Consortium on Complex Epilepsies.
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