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

International League Against Epilepsy Consortium on Complex Epilepsies; 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 Avbersek; Melanie Bahlo; Mark D. Baker; Ganna Balagura; Simona Balestrini; Carmen Barba; Karen Barboza; Fabrice Bartolomei; 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 R. Bobbili; Ingo Borggraefe; Christian Bosselmann; Vera Braatz; Jonathan P. Bradfield; Knut Brockmann; Lawrence C. Brody; Russell J. Buono; Robyn M. Busch; Hande Caglayan; 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 J. 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 J. Dlugos; Viola Doccini; Colin P. Doherty; Hany El-Naggar; Christian E. Elger; Colin A. Ellis; Johan G. Eriksson; Annika Faucon; Yen Chen A. Feng; Lisa Ferguson; Thomas N. Ferraro; Lorenzo Ferri; Martha Feucht; Mark 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; Tracy Glauser; Ethan Goldberg; Alicia Goldman; Tiziana Granata; David A. Greenberg; Renzo Guerrini; Namrata Gupta; Kevin F. Haas; Hakon Hakonarson; Kerstin Hallmann; Emadeldin Hassanin; Manu Hegde; Erin L. Heinzen; Ingo Helbig; Christian Hengsbach; Henrike O. Heyne; Shinichi Hirose; Edouard Hirsch; Helle Hjalgrim; Daniel P. Howrigan; Donald Hucks; Po Cheng Hung; Michele Iacomino; Lukas L. Imbach; Yushi Inoue; Atsushi Ishii; Jennifer Jamnadas-Khoda; Lara Jehi; Michael R. Johnson; Reetta Kälviäinen; Yoichiro Kamatani; Moien Kanaan; Masahiro Kanai; Anne Mari Kantanen; Bülent Kara; Symon M. Kariuki; Dalia Kasperavičiūte; Dorothee Kasteleijn-Nolst Trenite; Mitsuhiro Kato; Josua Kegele; Yeşim Kesim; Nathalie Khoueiry-Zgheib; Chontelle King; Heidi E. Kirsch; Karl M. Klein; Gerhard Kluger; Susanne Knake; Robert C. Knowlton; Bobby P.C. Koeleman; Amos D. Korczyn; Andreas Koupparis; Ioanna Kousiappa; Roland Krause; Martin Krenn; Heinz Krestel; Ilona Krey; Wolfram S. Kunz; Mitja I. Kurki; Gerhard Kurlemann; Ruben Kuzniecky; Patrick Kwan; Angelo Labate; Austin Lacey; Dennis Lal; Zied Landoulsi; Yu Lung Lau; Stephen Lauxmann; Stephanie L. Leech; Anna Elina Lehesjoki; Johannes R. Lemke; Holger Lerche; Gaetan Lesca; Costin Leu; Naomi Lewin; David Lewis-Smith; Gloria H.Y. Li; Qingqin S. Li; Laura Licchetta; Kuang Lin Lin; Dick Lindhout; Tarja Linnankivi; Iscia Lopes-Cendes; Daniel H. Lowenstein; Colin H.T. Lui; Francesca Madia; Sigurdur Magnusson; Anthony G. Marson; Patrick May; Christopher M. McGraw; Davide Mei; James L. Mills; Raffaella Minardi; Nasir Mirza; Rikke S. Møller; Anne M. Molloy; Martino Montomoli; Barbara Mostacci; Lorenzo Muccioli; Liu Lin Thio; Judith Weisenberg

doi:10.1038/s41588-023-01485-w

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

International League Against Epilepsy Consortium on Complex Epilepsies, 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 Avbersek, Melanie Bahlo, Mark D. Baker, Ganna Balagura, Simona Balestrini, Carmen Barba, Karen BarbozaFabrice Bartolomei, 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 R. Bobbili, Ingo Borggraefe, Christian Bosselmann, Vera Braatz, Jonathan P. Bradfield, Knut Brockmann, Lawrence C. Brody, Russell J. Buono, Robyn M. Busch, Hande Caglayan, 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 J. 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 J. Dlugos, Viola Doccini, Colin P. Doherty, Hany El-Naggar, Christian E. Elger, Colin A. Ellis, Johan G. Eriksson, Annika Faucon, Yen Chen A. Feng, Lisa Ferguson, Thomas N. Ferraro, Lorenzo Ferri, Martha Feucht, Mark 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, Tracy Glauser, Ethan Goldberg, Alicia Goldman, Tiziana Granata, David A. Greenberg, Renzo Guerrini, Namrata Gupta, Kevin F. Haas, Hakon Hakonarson, Kerstin Hallmann, Emadeldin Hassanin, Manu Hegde, Erin L. Heinzen, Ingo Helbig, Christian Hengsbach, Henrike O. Heyne, Shinichi Hirose, Edouard Hirsch, Helle Hjalgrim, Daniel P. Howrigan, Donald Hucks, Po Cheng Hung, Michele Iacomino, Lukas L. Imbach, Yushi Inoue, Atsushi Ishii, Jennifer Jamnadas-Khoda, Lara Jehi, Michael R. Johnson, Reetta Kälviäinen, Yoichiro Kamatani, Moien Kanaan, Masahiro Kanai, Anne Mari Kantanen, Bülent Kara, Symon M. Kariuki, Dalia Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Mitsuhiro Kato, Josua Kegele, Yeşim Kesim, Nathalie Khoueiry-Zgheib, Chontelle King, Heidi E. Kirsch, Karl M. Klein, Gerhard Kluger, Susanne Knake, Robert C. Knowlton, Bobby P.C. Koeleman, Amos D. Korczyn, Andreas Koupparis, Ioanna Kousiappa, Roland Krause, Martin Krenn, Heinz Krestel, Ilona Krey, Wolfram S. Kunz, Mitja I. Kurki, Gerhard Kurlemann, Ruben Kuzniecky, Patrick Kwan, Angelo Labate, Austin Lacey, Dennis Lal, Zied Landoulsi, Yu Lung Lau, Stephen Lauxmann, Stephanie L. Leech, Anna Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Gaetan Lesca, Costin Leu, Naomi Lewin, David Lewis-Smith, Gloria H.Y. Li, Qingqin S. Li, Laura Licchetta, Kuang Lin Lin, Dick Lindhout, Tarja Linnankivi, Iscia Lopes-Cendes, Daniel H. Lowenstein, Colin H.T. Lui, Francesca Madia, Sigurdur Magnusson, Anthony G. Marson, Patrick May, Christopher M. McGraw, Davide Mei, James L. Mills, Raffaella Minardi, Nasir Mirza, Rikke S. Møller, Anne M. Molloy, Martino Montomoli, Barbara Mostacci, Lorenzo Muccioli, Liu Lin Thio, Judith Weisenberg

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

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.

Original language	English
Pages (from-to)	1471-1482
Number of pages	12
Journal	Nature Genetics
Volume	55
Issue number	9
DOIs	https://doi.org/10.1038/s41588-023-01485-w
State	Published - Sep 2023

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10.1038/s41588-023-01485-w

Cite this

International League Against Epilepsy Consortium on Complex Epilepsies, 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., ... Weisenberg, J. (2023). GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nature Genetics, 55(9), 1471-1482. https://doi.org/10.1038/s41588-023-01485-w

@article{8f53175c770a427a8451e6007262e2af,

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

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.",

author = "{International League Against Epilepsy Consortium on Complex Epilepsies} and Remi Stevelink and Ciar{\'a}n Campbell and Siwei Chen and Bassel Abou-Khalil and Adesoji, {Oluyomi M.} and Zaid Afawi and Elisabetta Amadori and Alison Anderson and Joseph Anderson and Andrade, {Danielle M.} and Grazia Annesi and Pauls Auce and Andreja Avbersek and Melanie Bahlo and Baker, {Mark D.} and Ganna Balagura and Simona Balestrini and Carmen Barba and Karen Barboza and Fabrice Bartolomei and Thomas Bast and Larry Baum and Tobias Baumgartner and Bet{\"u}l Baykan and Nerses Bebek and Becker, {Albert J.} and Felicitas Becker and Bennett, {Caitlin A.} and Bianca Berghuis and Berkovic, {Samuel F.} and Ahmad Beydoun and Claudia Bianchini and Francesca Bisulli and Ilan Blatt and Bobbili, {Dheeraj R.} and Ingo Borggraefe and Christian Bosselmann and Vera Braatz and Bradfield, {Jonathan P.} and Knut Brockmann and Brody, {Lawrence C.} and Buono, {Russell J.} and Busch, {Robyn M.} and Hande Caglayan and Ellen Campbell and Laura Canafoglia and Christina Canavati and Cascino, {Gregory D.} and Barbara Castellotti and Catarino, {Claudia B.} and Cavalleri, {Gianpiero L.} and Felecia Cerrato and Francine Chassoux and Cherny, {Stacey S.} and Cheung, {Ching Lung} and Krishna Chinthapalli and Chou, {I. Jun} and Chung, {Seo Kyung} and Claire Churchhouse and Clark, {Peggy O.} and Cole, {Andrew J.} and Alastair Compston and Antonietta Coppola and Mahgenn Cosico and Patrick Cossette and Craig, {John J.} and Caroline Cusick and Daly, {Mark J.} and Davis, {Lea K.} and {de Haan}, {Gerrit Jan} and Norman Delanty and Chantal Depondt and Philippe Derambure and Orrin Devinsky and {Di Vito}, Lidia and Dlugos, {Dennis J.} and Viola Doccini and Doherty, {Colin P.} and Hany El-Naggar and Elger, {Christian E.} and Ellis, {Colin A.} and Eriksson, {Johan G.} and Annika Faucon and Feng, {Yen Chen A.} and Lisa Ferguson and Ferraro, {Thomas N.} and Lorenzo Ferri and Martha Feucht and Mark Fitzgerald and Beata Fonferko-Shadrach and Francesco Fortunato and Silvana Franceschetti and Andre Franke and French, {Jacqueline A.} and Elena Freri and Monica Gagliardi and Antonio Gambardella and Geller, {Eric B.} and Tania Giangregorio and Leif Gjerstad and Tracy Glauser and Ethan Goldberg and Alicia Goldman and Tiziana Granata and Greenberg, {David A.} and Renzo Guerrini and Namrata Gupta and Haas, {Kevin F.} and Hakon Hakonarson and Kerstin Hallmann and Emadeldin Hassanin and Manu Hegde and Heinzen, {Erin L.} and Ingo Helbig and Christian Hengsbach and Heyne, {Henrike O.} and Shinichi Hirose and Edouard Hirsch and Helle Hjalgrim and Howrigan, {Daniel P.} and Donald Hucks and Hung, {Po Cheng} and Michele Iacomino and Imbach, {Lukas L.} and Yushi Inoue and Atsushi Ishii and Jennifer Jamnadas-Khoda and Lara Jehi and Johnson, {Michael R.} and Reetta K{\"a}lvi{\"a}inen and Yoichiro Kamatani and Moien Kanaan and Masahiro Kanai and Kantanen, {Anne Mari} and B{\"u}lent Kara and Kariuki, {Symon M.} and Dalia Kasperavi{\v c}iūte and {Kasteleijn-Nolst Trenite}, Dorothee and Mitsuhiro Kato and Josua Kegele and Ye{\c s}im Kesim and Nathalie Khoueiry-Zgheib and Chontelle King and Kirsch, {Heidi E.} and Klein, {Karl M.} and Gerhard Kluger and Susanne Knake and Knowlton, {Robert C.} and Koeleman, {Bobby P.C.} and Korczyn, {Amos D.} and Andreas Koupparis and Ioanna Kousiappa and Roland Krause and Martin Krenn and Heinz Krestel and Ilona Krey and Kunz, {Wolfram S.} and Kurki, {Mitja I.} and Gerhard Kurlemann and Ruben Kuzniecky and Patrick Kwan and Angelo Labate and Austin Lacey and Dennis Lal and Zied Landoulsi and Lau, {Yu Lung} and Stephen Lauxmann and Leech, {Stephanie L.} and Lehesjoki, {Anna Elina} and Lemke, {Johannes R.} and Holger Lerche and Gaetan Lesca and Costin Leu and Naomi Lewin and David Lewis-Smith and Li, {Gloria H.Y.} and Li, {Qingqin S.} and Laura Licchetta and Lin, {Kuang Lin} and Dick Lindhout and Tarja Linnankivi and Iscia Lopes-Cendes and Lowenstein, {Daniel H.} and Lui, {Colin H.T.} and Francesca Madia and Sigurdur Magnusson and Marson, {Anthony G.} and Patrick May and McGraw, {Christopher M.} and Davide Mei and Mills, {James L.} and Raffaella Minardi and Nasir Mirza and M{\o}ller, {Rikke S.} and Molloy, {Anne M.} and Martino Montomoli and Barbara Mostacci and Lorenzo Muccioli and Thio, {Liu Lin} and Judith Weisenberg",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = sep,

doi = "10.1038/s41588-023-01485-w",

language = "English",

volume = "55",

pages = "1471--1482",

journal = "Nature Genetics",

issn = "1061-4036",

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International League Against Epilepsy Consortium on Complex Epilepsies, 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, CL, Chinthapalli, K, Chou, IJ, Chung, SK, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, GJ, 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, YCA, 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, PC, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kälviäinen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, AM, Kara, B, Kariuki, SM, Kasperavičiūte, 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, YL, Lauxmann, S, Leech, SL, Lehesjoki, AE, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GHY, Li, QS, Licchetta, L, Lin, KL, 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, Møller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Thio, LL & Weisenberg, J 2023, 'GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture', Nature Genetics, vol. 55, no. 9, pp. 1471-1482. https://doi.org/10.1038/s41588-023-01485-w

TY - JOUR

T1 - GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

AU - International League Against Epilepsy Consortium on Complex Epilepsies

AU - Stevelink, Remi

AU - Campbell, Ciarán

AU - Chen, Siwei

AU - Abou-Khalil, Bassel

AU - Adesoji, Oluyomi M.

AU - Afawi, Zaid

AU - Amadori, Elisabetta

AU - Anderson, Alison

AU - Anderson, Joseph

AU - Andrade, Danielle M.

AU - Annesi, Grazia

AU - Auce, Pauls

AU - Avbersek, Andreja

AU - Bahlo, Melanie

AU - Baker, Mark D.

AU - Balagura, Ganna

AU - Balestrini, Simona

AU - Barba, Carmen

AU - Barboza, Karen

AU - Bartolomei, Fabrice

AU - Bast, Thomas

AU - Baum, Larry

AU - Baumgartner, Tobias

AU - Baykan, Betül

AU - Bebek, Nerses

AU - Becker, Albert J.

AU - Becker, Felicitas

AU - Bennett, Caitlin A.

AU - Berghuis, Bianca

AU - Berkovic, Samuel F.

AU - Beydoun, Ahmad

AU - Bianchini, Claudia

AU - Bisulli, Francesca

AU - Blatt, Ilan

AU - Bobbili, Dheeraj R.

AU - Borggraefe, Ingo

AU - Bosselmann, Christian

AU - Braatz, Vera

AU - Bradfield, Jonathan P.

AU - Brockmann, Knut

AU - Brody, Lawrence C.

AU - Buono, Russell J.

AU - Busch, Robyn M.

AU - Caglayan, Hande

AU - Campbell, Ellen

AU - Canafoglia, Laura

AU - Canavati, Christina

AU - Cascino, Gregory D.

AU - Castellotti, Barbara

AU - Catarino, Claudia B.

AU - Cavalleri, Gianpiero L.

AU - Cerrato, Felecia

AU - Chassoux, Francine

AU - Cherny, Stacey S.

AU - Cheung, Ching Lung

AU - Chinthapalli, Krishna

AU - Chou, I. Jun

AU - Chung, Seo Kyung

AU - Churchhouse, Claire

AU - Clark, Peggy O.

AU - Cole, Andrew J.

AU - Compston, Alastair

AU - Coppola, Antonietta

AU - Cosico, Mahgenn

AU - Cossette, Patrick

AU - Craig, John J.

AU - Cusick, Caroline

AU - Daly, Mark J.

AU - Davis, Lea K.

AU - de Haan, Gerrit Jan

AU - Delanty, Norman

AU - Depondt, Chantal

AU - Derambure, Philippe

AU - Devinsky, Orrin

AU - Di Vito, Lidia

AU - Dlugos, Dennis J.

AU - Doccini, Viola

AU - Doherty, Colin P.

AU - El-Naggar, Hany

AU - Elger, Christian E.

AU - Ellis, Colin A.

AU - Eriksson, Johan G.

AU - Faucon, Annika

AU - Feng, Yen Chen A.

AU - Ferguson, Lisa

AU - Ferraro, Thomas N.

AU - Ferri, Lorenzo

AU - Feucht, Martha

AU - Fitzgerald, Mark

AU - Fonferko-Shadrach, Beata

AU - Fortunato, Francesco

AU - Franceschetti, Silvana

AU - Franke, Andre

AU - French, Jacqueline A.

AU - Freri, Elena

AU - Gagliardi, Monica

AU - Gambardella, Antonio

AU - Geller, Eric B.

AU - Giangregorio, Tania

AU - Gjerstad, Leif

AU - Glauser, Tracy

AU - Goldberg, Ethan

AU - Goldman, Alicia

AU - Granata, Tiziana

AU - Greenberg, David A.

AU - Guerrini, Renzo

AU - Gupta, Namrata

AU - Haas, Kevin F.

AU - Hakonarson, Hakon

AU - Hallmann, Kerstin

AU - Hassanin, Emadeldin

AU - Hegde, Manu

AU - Heinzen, Erin L.

AU - Helbig, Ingo

AU - Hengsbach, Christian

AU - Heyne, Henrike O.

AU - Hirose, Shinichi

AU - Hirsch, Edouard

AU - Hjalgrim, Helle

AU - Howrigan, Daniel P.

AU - Hucks, Donald

AU - Hung, Po Cheng

AU - Iacomino, Michele

AU - Imbach, Lukas L.

AU - Inoue, Yushi

AU - Ishii, Atsushi

AU - Jamnadas-Khoda, Jennifer

AU - Jehi, Lara

AU - Johnson, Michael R.

AU - Kälviäinen, Reetta

AU - Kamatani, Yoichiro

AU - Kanaan, Moien

AU - Kanai, Masahiro

AU - Kantanen, Anne Mari

AU - Kara, Bülent

AU - Kariuki, Symon M.

AU - Kasperavičiūte, Dalia

AU - Kasteleijn-Nolst Trenite, Dorothee

AU - Kato, Mitsuhiro

AU - Kegele, Josua

AU - Kesim, Yeşim

AU - Khoueiry-Zgheib, Nathalie

AU - King, Chontelle

AU - Kirsch, Heidi E.

AU - Klein, Karl M.

AU - Kluger, Gerhard

AU - Knake, Susanne

AU - Knowlton, Robert C.

AU - Koeleman, Bobby P.C.

AU - Korczyn, Amos D.

AU - Koupparis, Andreas

AU - Kousiappa, Ioanna

AU - Krause, Roland

AU - Krenn, Martin

AU - Krestel, Heinz

AU - Krey, Ilona

AU - Kunz, Wolfram S.

AU - Kurki, Mitja I.

AU - Kurlemann, Gerhard

AU - Kuzniecky, Ruben

AU - Kwan, Patrick

AU - Labate, Angelo

AU - Lacey, Austin

AU - Lal, Dennis

AU - Landoulsi, Zied

AU - Lau, Yu Lung

AU - Lauxmann, Stephen

AU - Leech, Stephanie L.

AU - Lehesjoki, Anna Elina

AU - Lemke, Johannes R.

AU - Lerche, Holger

AU - Lesca, Gaetan

AU - Leu, Costin

AU - Lewin, Naomi

AU - Lewis-Smith, David

AU - Li, Gloria H.Y.

AU - Li, Qingqin S.

AU - Licchetta, Laura

AU - Lin, Kuang Lin

AU - Lindhout, Dick

AU - Linnankivi, Tarja

AU - Lopes-Cendes, Iscia

AU - Lowenstein, Daniel H.

AU - Lui, Colin H.T.

AU - Madia, Francesca

AU - Magnusson, Sigurdur

AU - Marson, Anthony G.

AU - May, Patrick

AU - McGraw, Christopher M.

AU - Mei, Davide

AU - Mills, James L.

AU - Minardi, Raffaella

AU - Mirza, Nasir

AU - Møller, Rikke S.

AU - Molloy, Anne M.

AU - Montomoli, Martino

AU - Mostacci, Barbara

AU - Muccioli, Lorenzo

AU - Thio, Liu Lin

AU - Weisenberg, Judith

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85169457451&partnerID=8YFLogxK

U2 - 10.1038/s41588-023-01485-w

DO - 10.1038/s41588-023-01485-w

M3 - Article

C2 - 37653029

AN - SCOPUS:85169457451

SN - 1061-4036

VL - 55

SP - 1471

EP - 1482

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

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