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

Remi Stevelink; Ciaran 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; Betul 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 Kalviainen; Yoichiro Kamatani; Moien Kanaan; Masahiro Kanai; Anne-Mari Kantanen; Bulent Kara; Symon M. Kariuki; Dalia Kasperaviciute; Dorothee Kasteleijn-Nolst Trenite; Mitsuhiro Kato; Josua Kegele; Yescommaim 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. Moller; Anne M. Molloy; Martino Montomoli; Barbara Mostacci; Lorenzo Muccioli; Hiltrud Muhle; Karen Mueller-Schlueter; Imad M. Najm; Wassim Nasreddine; Benjamin M. Neale; Bernd Neubauer; Charles R. J. C. Newton; Markus M. Noethen; Michael Nothnagel; Peter Nuernberg; Terence J. O'Brien; Yukinori Okada; Elias Olafsson; Karen L. Oliver; Cigdem Ozkara; Aarno Palotie; Faith Pangilinan; Savvas S. Papacostas; Elena Parrini; Carlos N. Pato; Michele T. Pato; Manuela Pendziwiat; Slave Petrovski; William O. Pickrell; Rebecca Pinsky; Tommaso Pippucci; Annapurna Poduri; Federica Pondrelli; Rob H. W. Powell; Michael Privitera; Annika Rademacher; Rodney Radtke; Francesca Ragona; Sarah Rau; Mark I. Rees; Brigid M. Regan; Philipp S. Reif; Sylvain Rhelms; Antonella Riva; Felix Rosenow; Philippe Ryvlin; Anni Saarela; Lynette G. Sadleir; Josemir W. Sander; Thomas Sander; Marcello Scala; Theresa Scattergood; Steven C. Schachter; Christoph J. Schankin; Ingrid E. Scheffer; Bettina Schmitz; Susanne Schoch; Susanne Schubert-Bast; Andreas Schulze-Bonhage; Paolo Scudieri; Pak Sham; Beth R. Sheidley; Jerry J. Shih; Graeme J. Sills; Sanjay M. Sisodiya; Michael C. Smith; Philip E. Smith; Anja C. M. Sonsma; Doug Speed; Michael R. Sperling; Hreinn Stefansson; Kari Stefansson; Bernhard J. Steinhoff; Ulrich Stephani; William C. Stewart; Carlotta Stipa; Pasquale Striano; Hans Stroink; Adam Strzelczyk; Rainer Surges; Toshimitsu Suzuki; K. Meng Tan; R. S. Taneja; George A. Tanteles; Erik Tauboll; Liu Lin Thio; G. Neil Thomas; Rhys H. Thomas; Oskari Timonen; Paolo Tinuper; Marian Todaro; Pinar Topaloglu; Rossana Tozzi; Meng-Han Tsai; Birute Tumiene; Dilsad Turkdogan; Unnur Unnsteinsdottir; Algirdas Utkus; Priya Vaidiswaran; Luc Valton; Andreas van Baalen; Annalisa Vetro; Eileen P. G. Vining; Frank Visscher; Sophie von Brauchitsch; Randi von Wrede; Ryan G. Wagner; Yvonne G. Weber; Sarah Weckhuysen; Judith Weisenberg; Michael Weller; Peter Widdess-Walsh; Markus Wolff; Stefan Wolking; David Wu; Kazuhiro Yamakawa; Wanling Yang; Zuhal Yapici; Emrah Yucesan; Sara Zagaglia; Felix Zahnert; Federico Zara; Wei Zhou; Fritz Zimprich; Gabor Zsurka; Quratulain Zulfiqar Ali; Int League Against Epilepsy

doi:10.1038/s41588-023-01485-w

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

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

Remi Stevelink, Ciaran Campbell, Siwei Chen, Bassel Abou-Khalil, Oluyomi M. Adesoji, Zaid Afawi, Elisabetta Amadori, Alison Anderson, Joseph Anderson, Danielle M. Andrade, …

Nature genetics, Vol.55(9), pp.1471-1482

01/09/2023

DOI: https://doi.org/10.1038/s41588-023-01485-w

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https://hdl.handle.net/10523/22348

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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.

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Record Identifier: 9926495506401891
Title: GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Creators: Remi Stevelink
Ciaran 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
Betul 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 Kalviainen
Yoichiro Kamatani
Moien Kanaan
Masahiro Kanai
Anne-Mari Kantanen
Bulent Kara
Symon M. Kariuki
Dalia Kasperaviciute
Dorothee Kasteleijn-Nolst Trenite
Mitsuhiro Kato
Josua Kegele
Yescommaim 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. Moller
Anne M. Molloy
Martino Montomoli
Barbara Mostacci
Lorenzo Muccioli
Hiltrud Muhle
Karen Mueller-Schlueter
Imad M. Najm
Wassim Nasreddine
Benjamin M. Neale
Bernd Neubauer
Charles R. J. C. Newton
Markus M. Noethen
Michael Nothnagel
Peter Nuernberg
Terence J. O'Brien
Yukinori Okada
Elias Olafsson
Karen L. Oliver
Cigdem Ozkara
Aarno Palotie
Faith Pangilinan
Savvas S. Papacostas
Elena Parrini
Carlos N. Pato
Michele T. Pato
Manuela Pendziwiat
Slave Petrovski
William O. Pickrell
Rebecca Pinsky
Tommaso Pippucci
Annapurna Poduri
Federica Pondrelli
Rob H. W. Powell
Michael Privitera
Annika Rademacher
Rodney Radtke
Francesca Ragona
Sarah Rau
Mark I. Rees
Brigid M. Regan
Philipp S. Reif
Sylvain Rhelms
Antonella Riva
Felix Rosenow
Philippe Ryvlin
Anni Saarela
Lynette G. Sadleir
Josemir W. Sander
Thomas Sander
Marcello Scala
Theresa Scattergood
Steven C. Schachter
Christoph J. Schankin
Ingrid E. Scheffer
Bettina Schmitz
Susanne Schoch
Susanne Schubert-Bast
Andreas Schulze-Bonhage
Paolo Scudieri
Pak Sham
Beth R. Sheidley
Jerry J. Shih
Graeme J. Sills
Sanjay M. Sisodiya
Michael C. Smith
Philip E. Smith
Anja C. M. Sonsma
Doug Speed
Michael R. Sperling
Hreinn Stefansson
Kari Stefansson
Bernhard J. Steinhoff
Ulrich Stephani
William C. Stewart
Carlotta Stipa
Pasquale Striano
Hans Stroink
Adam Strzelczyk
Rainer Surges
Toshimitsu Suzuki
K. Meng Tan
R. S. Taneja
George A. Tanteles
Erik Tauboll
Liu Lin Thio
G. Neil Thomas
Rhys H. Thomas
Oskari Timonen
Paolo Tinuper
Marian Todaro
Pinar Topaloglu
Rossana Tozzi
Meng-Han Tsai
Birute Tumiene
Dilsad Turkdogan
Unnur Unnsteinsdottir
Algirdas Utkus
Priya Vaidiswaran
Luc Valton
Andreas van Baalen
Annalisa Vetro
Eileen P. G. Vining
Frank Visscher
Sophie von Brauchitsch
Randi von Wrede
Ryan G. Wagner
Yvonne G. Weber
Sarah Weckhuysen
Judith Weisenberg
Michael Weller
Peter Widdess-Walsh
Markus Wolff
Stefan Wolking
David Wu
Kazuhiro Yamakawa
Wanling Yang
Zuhal Yapici
Emrah Yucesan
Sara Zagaglia
Felix Zahnert
Federico Zara
Wei Zhou
Fritz Zimprich
Gabor Zsurka
Quratulain Zulfiqar Ali
Int League Against Epilepsy
Publication Details: Nature genetics, Vol.55(9), pp.1471-1482
Academic Unit: Paediatrics and Child Health (UOW)
Publisher: NATURE PORTFOLIO
Grant note: 1616091 / 'Vrienden WKZ' fund 1091593 / National Health and Medical Research Council (NHMRC) of Australia Bristol Myers Squibb; Bristol-Myers Squibb National Human Genome Research Institute (NHGRI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) Epilepsy Society, UK MR/S02638X/1 / UKRI MRC award; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 16/RC/3948 / Science Foundation Ireland (SFI); Science Foundation Ireland Janssen Biotech; Johnson & Johnson; Johnson & Johnson USA; Janssen Biotech Inc 2013/07559-3 / Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) Sanofi US Services AstraZeneca UK; AstraZeneca NIHR Imperial Biomedical Research Center (BRC) support AbbVie Biogen MA Academy of Finland; Research Council of Finland European Union; European Union (EU) Novartis AG 279062 / European Union; European Union (EU) INTER/DFG/21/16394868 MechEPI2 / FNR; Luxembourg National Research Fund FOR-2715; NO755/6-1; NO755/13-1 / European Regional Development Fund of the German Research Foundation Pfizer APP533086 / University of Melbourne U01MH105641 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA HUS 4685/31/2016; UH 4386/31/2016 / Business Finland FOR-2715 / Fonds National de la Recherche Luxembourg; Luxembourg National Research Fund 203914/Z/16/Z / Wellcome Clinical Ph.D. Fellowship on the 4Ward North program Celgene International II Sarl; Bristol-Myers Squibb; Celgene Corporation Celgene Corporation; Bristol-Myers Squibb Merck Sharp Dohme Corp; Merck & Company 27100416 / Bone Health Fund and Research Grants Council-Early Career Scheme NIHR Biomedical Research Centers APP1195236 / NHMRC; National Health and Medical Research Council (NHMRC) of Australia Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard Eunice Kennedy Shriver National Institute of Child Health and Human Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Maze Therapeutics National Heart, Lung and Blood Institute (NHLBI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 084730 / Wellcome Trust Muir Maxwell Trust GlaxoSmithKline Intellectual Property Development APP533086 / Australian Commonwealth Government; Australian Government THL Boehringer Ingelheim UM1 HG008895; 5U01HG009088-02 / NHGRI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) Genentech; Roche Holding
Date published ; e-published: 01/09/2023
Language: English
Resource Type ; Subtype: Journal article