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Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations
Remi Stevelink 
,
Jurjen J. Luykx,
Bochao D. Lin,
Costin Leu,
Dennis Lal,
Alexander W. Smith,
Dick Schijven,
Johannes A. Carpay,
Koen Rademaker,
Roiza A. Rodrigues Baldez,
Orrin Devinsky ,
Kees P. J. Braun,
Floor E. Jansen,
Dirk J. A. Smit,
Bobby P. C. Koeleman,
Bassel Abou‐Khalil,
Pauls Auce,
Andreja Avbersek,
Melanie Bahlo,
David J. Balding,
Thomas Bast,
Larry Baum,
Albert J. Becker,
Felicitas Becker,
Bianca Berghuis,
Samuel F. Berkovic,
Katja E. Boysen,
Jonathan P. Bradfield,
Lawrence C. Brody,
Russell J. Buono,
Ellen Campbell,
Gregory D. Cascino,
Claudia B. Catarino,
Gianpiero L. Cavalleri,
Stacey S. Cherny,
Krishna Chinthapalli,
Alison J. Coffey,
Alastair Compston,
Antonietta Coppola,
Patrick Cossette,
John J. Craig,
Gerrit‐Jan Haan,
Peter De Jonghe,
Carolien G. F. Kovel,
Norman Delanty,
Chantal Depondt,
Dennis J. Dlugos,
Colin P. Doherty,
Christian E. Elger,
Johan G. Eriksson,
Thomas N. Ferraro,
Martha Feucht,
Ben Francis,
Andre Franke,
Jacqueline A. French,
Saskia Freytag,
Verena Gaus,
Eric B. Geller,
Christian Gieger,
Tracy Glauser,
Simon Glynn,
David B. Goldstein,
Hongsheng Gui,
Youling Guo,
Kevin F. Haas,
Hakon Hakonarson,
Kerstin Hallmann,
Sheryl Haut,
Erin L. Heinzen,
Ingo Helbig,
Christian Hengsbach,
Helle Hjalgrim,
Michele Iacomino,
Andrés Ingason,
Jennifer Jamnadas‐Khoda,
Michael R. Johnson,
Reetta Kälviäinen,
Anne‐Mari Kantanen,
Dalia Kasperavičiūte,
Dorothee Kasteleijn‐Nolst Trenite,
Heidi E. Kirsch,
Robert C. Knowlton,
Roland Krause,
Martin Krenn,
Wolfram S. Kunz,
Ruben Kuzniecky,
Patrick Kwan,
Yu‐Lung Lau,
Anna‐Elina Lehesjoki,
Holger Lerche,
Wolfgang Lieb,
Dick Lindhout,
Warren D. Lo,
Iscia Lopes‐Cendes,
Daniel H. Lowenstein,
Alberto Malovini,
Anthony G. Marson,
Thomas Mayer,
Mark McCormack,
James L. Mills,
Nasir Mirza,
Martina Moerzinger,
Rikke S. Møller,
Anne M. Molloy,
Hiltrud Muhle,
Mark Newton,
Ping‐Wing Ng,
Markus M. Nöthen,
Peter Nürnberg,
Terence J. O’Brien,
Karen L. Oliver,
Aarno Palotie,
Faith Pangilinan,
Sarah Peter,
Slavé Petrovski,
Annapurna Poduri,
Michael Privitera,
Rodney Radtke,
Sarah Rau,
Philipp S. Reif,
Eva M. Reinthaler,
Felix Rosenow,
Josemir W. Sander,
Thomas Sander,
Theresa Scattergood,
Steven C. Schachter,
Christoph J. Schankin,
Ingrid E. Scheffer,
Bettina Schmitz,
Susanne Schoch,
Pak C. Sham,
Jerry J. Shih,
Graeme J. Sills,
Sanjay M. Sisodiya,
Lisa Slattery,
David F. Smith,
Michael C. Smith,
Philip E. Smith,
Anja C. M. Sonsma,
Doug Speed,
Michael R. Sperling,
Bernhard J. Steinhoff,
Ulrich Stephani,
Konstantin Strauch,
Pasquale Striano,
Hans Stroink,
Rainer Surges,
K. Meng Tan,
Liu Lin Thio,
G. Neil Thomas,
Marian Todaro,
Rossana Tozzi,
Maria S. Vari,
Eileen P. G. Vining,
Frank Visscher,
Sarah Spiczak,
Nicole M. Walley,
Yvonne G. Weber,
Zhi Wei,
Ruta Mameniskiene,
Judith Weisenberg,
Christopher D. Whelan,
Peter Widdess‐Walsh,
Markus Wolff,
Stefan Wolking,
Wanling Yang,
Federico Zara,
Fritz Zimprich,
Yen‐Chen Anne Feng,
Daniel P. Howrigan,
Liam E. Abbott,
Katherine Tashman,
Felecia Cerrato,
Dennis Lal,
Claire Churchhouse,
Namrata Gupta,
Stacey B. Gabriel,
Mark J. Daly,
Eric S. Lander,
Benjamin M. Neale,
Samuel F. Berkovic,
Holger Lerche,
David B. Goldstein,
Daniel H. Lowenstein,
Gianpiero L. Cavalleri,
Patrick Cossette,
Chris Cotsapas,
Peter De Jonghe,
Tracy Dixon‐Salazar,
Renzo Guerrini,
Hakon Hakonarson,
Erin L. Heinzen,
Ingo Helbig,
Patrick Kwan,
Slavé Petrovski,
Sitharthan Kamalakaran,
Sanjay M. Sisodiya,
Randy Stewart,
Sarah Weckhuysen,
Dennis J. Dlugos,
Ingrid E. Scheffer,
Pasquale Striano,
Catharine Freyer,
Roland Krause,
Patrick May,
Kevin McKenna,
Brigid M. Regan,
Susannah T. Bellows,
Caitlin A. Bennett,
Esther M.C. Johns,
Alexandra Macdonald,
Hannah Shilling,
Rosemary Burgess,
Dorien Weckhuysen,
Melanie Bahlo,
Terence J. O'Brien,
Marian Todaro,
Hannah Stamberger,
Chantal Depondt,
Danielle M. Andrade,
Tara R. Sadoway,
Kelly Mo,
Heinz Krestel,
Sabina Gallati,
Savvas S. Papacostas,
Ioanna Kousiappa,
George A. Tanteles,
Katalin Štěrbová,
Markéta Vlčková,
Lucie Sedláčková,
Petra Laššuthová,
Karl Martin Klein,
Felix Rosenow,
Philipp S. Reif,
Susanne Knake,
Wolfram S. Kunz,
Gábor Zsurka,
Christian E. Elger,
Jürgen Bauer,
Michael Rademacher,
Manuela Pendziwiat,
Hiltrud Muhle,
Annika Rademacher,
Andreas Baalen,
Sarah Spiczak,
Ulrich Stephani,
Zaid Afawi,
Amos D. Korczyn,
Moien Kanaan,
Christina Canavati,
Gerhard Kurlemann,
Karen Müller‐Schlüter,
Gerhard Kluger,
Martin Häusler,
Ilan Blatt,
Johannes R. Lemke,
Ilona Krey,
Yvonne G. Weber,
Stefan Wolking,
Felicitas Becker,
Christian Hengsbach,
Sarah Rau,
Ana F. Maisch,
Bernhard J. Steinhoff,
Andreas Schulze‐Bonhage,
Susanne Schubert‐Bast,
Herbert Schreiber,
Ingo Borggräfe,
Christoph J. Schankin,
Thomas Mayer,
Rudolf Korinthenberg,
Knut Brockmann,
Dieter Dennig,
Rene Madeleyn,
Reetta Kälviäinen,
Pia Auvinen,
Anni Saarela,
Tarja Linnankivi,
Anna‐Elina Lehesjoki,
Mark I. Rees,
Seo‐Kyung Chung,
William O. Pickrell,
Robert Powell,
Natascha Schneider,
Simona Balestrini,
Sara Zagaglia,
Vera Braatz,
Anthony G. Marson,
Michael R. Johnson,
Pauls Auce,
Graeme J. Sills,
Larry W. Baum,
Pak C. Sham,
Stacey S. Cherny,
Colin H.T. Lui,
Nina Barišić,
Norman Delanty,
Colin P. Doherty,
Arif Shukralla,
Mark McCormack,
Hany El‐Naggar,
Laura Canafoglia,
Silvana Franceschetti,
Barbara Castellotti,
Tiziana Granata,
Federico Zara,
Michele Iacomino,
Francesca Madia,
Maria Stella Vari,
Maria Margherita Mancardi,
Vincenzo Salpietro,
Francesca Bisulli,
Paolo Tinuper,
Laura Licchetta,
Tommaso Pippucci,
Carlotta Stipa,
Raffaella Minardi,
Antonio Gambardella,
Angelo Labate,
Grazia Annesi,
Lorella Manna,
Monica Gagliardi,
Elena Parrini,
Davide Mei,
Annalisa Vetro,
Claudia Bianchini,
Martino Montomoli,
Viola Doccini,
Carla Marini,
Toshimitsu Suzuki,
Yushi Inoue,
Kazuhiro Yamakawa,
Birute Tumiene,
Lynette G. Sadleir,
Chontelle King,
Emily Mountier,
S. Hande Caglayan,
Mutluay Arslan,
Zuhal Yapıcı,
Uluc Yis,
Pınar Topaloglu,
Bulent Kara,
Dilsad Turkdogan,
Aslı Gundogdu‐Eken,
Nerses Bebek,
Sibel Uğur‐İşeri,
Betül Baykan,
Barış Salman,
Garen Haryanyan,
Emrah Yücesan,
Yeşim Kesim,
Çiğdem Özkara,
Annapurna Poduri,
Russell J. Buono,
Thomas N. Ferraro,
Michael R. Sperling,
Warren Lo,
Michael Privitera,
Jacqueline A. French,
Steven Schachter,
Ruben I. Kuzniecky,
Manu Hegde,
Pouya Khankhanian,
Katherine L. Helbig,
Colin A. Ellis,
(International League Against Epilepsy Consortium on Complex Epilepsies),
(Epi25 Collaborative)
,
Jurjen J. Luykx,
Bochao D. Lin,
Costin Leu,
Dennis Lal,
Alexander W. Smith,
Dick Schijven,
Johannes A. Carpay,
Koen Rademaker,
Roiza A. Rodrigues Baldez,
Orrin Devinsky ,
Kees P. J. Braun,
Floor E. Jansen,
Dirk J. A. Smit,
Bobby P. C. Koeleman,
Bassel Abou‐Khalil,
Pauls Auce,
Andreja Avbersek,
Melanie Bahlo,
David J. Balding,
Thomas Bast,
Larry Baum,
Albert J. Becker,
Felicitas Becker,
Bianca Berghuis,
Samuel F. Berkovic,
Katja E. Boysen,
Jonathan P. Bradfield,
Lawrence C. Brody,
Russell J. Buono,
Ellen Campbell,
Gregory D. Cascino,
Claudia B. Catarino,
Gianpiero L. Cavalleri,
Stacey S. Cherny,
Krishna Chinthapalli,
Alison J. Coffey,
Alastair Compston,
Antonietta Coppola,
Patrick Cossette,
John J. Craig,
Gerrit‐Jan Haan,
Peter De Jonghe,
Carolien G. F. Kovel,
Norman Delanty,
Chantal Depondt,
Dennis J. Dlugos,
Colin P. Doherty,
Christian E. Elger,
Johan G. Eriksson,
Thomas N. Ferraro,
Martha Feucht,
Ben Francis,
Andre Franke,
Jacqueline A. French,
Saskia Freytag,
Verena Gaus,
Eric B. Geller,
Christian Gieger,
Tracy Glauser,
Simon Glynn,
David B. Goldstein,
Hongsheng Gui,
Youling Guo,
Kevin F. Haas,
Hakon Hakonarson,
Kerstin Hallmann,
Sheryl Haut,
Erin L. Heinzen,
Ingo Helbig,
Christian Hengsbach,
Helle Hjalgrim,
Michele Iacomino,
Andrés Ingason,
Jennifer Jamnadas‐Khoda,
Michael R. Johnson,
Reetta Kälviäinen,
Anne‐Mari Kantanen,
Dalia Kasperavičiūte,
Dorothee Kasteleijn‐Nolst Trenite,
Heidi E. Kirsch,
Robert C. Knowlton,
Roland Krause,
Martin Krenn,
Wolfram S. Kunz,
Ruben Kuzniecky,
Patrick Kwan,
Yu‐Lung Lau,
Anna‐Elina Lehesjoki,
Holger Lerche,
Wolfgang Lieb,
Dick Lindhout,
Warren D. Lo,
Iscia Lopes‐Cendes,
Daniel H. Lowenstein,
Alberto Malovini,
Anthony G. Marson,
Thomas Mayer,
Mark McCormack,
James L. Mills,
Nasir Mirza,
Martina Moerzinger,
Rikke S. Møller,
Anne M. Molloy,
Hiltrud Muhle,
Mark Newton,
Ping‐Wing Ng,
Markus M. Nöthen,
Peter Nürnberg,
Terence J. O’Brien,
Karen L. Oliver,
Aarno Palotie,
Faith Pangilinan,
Sarah Peter,
Slavé Petrovski,
Annapurna Poduri,
Michael Privitera,
Rodney Radtke,
Sarah Rau,
Philipp S. Reif,
Eva M. Reinthaler,
Felix Rosenow,
Josemir W. Sander,
Thomas Sander,
Theresa Scattergood,
Steven C. Schachter,
Christoph J. Schankin,
Ingrid E. Scheffer,
Bettina Schmitz,
Susanne Schoch,
Pak C. Sham,
Jerry J. Shih,
Graeme J. Sills,
Sanjay M. Sisodiya,
Lisa Slattery,
David F. Smith,
Michael C. Smith,
Philip E. Smith,
Anja C. M. Sonsma,
Doug Speed,
Michael R. Sperling,
Bernhard J. Steinhoff,
Ulrich Stephani,
Konstantin Strauch,
Pasquale Striano,
Hans Stroink,
Rainer Surges,
K. Meng Tan,
Liu Lin Thio,
G. Neil Thomas,
Marian Todaro,
Rossana Tozzi,
Maria S. Vari,
Eileen P. G. Vining,
Frank Visscher,
Sarah Spiczak,
Nicole M. Walley,
Yvonne G. Weber,
Zhi Wei,
Ruta Mameniskiene,
Judith Weisenberg,
Christopher D. Whelan,
Peter Widdess‐Walsh,
Markus Wolff,
Stefan Wolking,
Wanling Yang,
Federico Zara,
Fritz Zimprich,
Yen‐Chen Anne Feng,
Daniel P. Howrigan,
Liam E. Abbott,
Katherine Tashman,
Felecia Cerrato,
Dennis Lal,
Claire Churchhouse,
Namrata Gupta,
Stacey B. Gabriel,
Mark J. Daly,
Eric S. Lander,
Benjamin M. Neale,
Samuel F. Berkovic,
Holger Lerche,
David B. Goldstein,
Daniel H. Lowenstein,
Gianpiero L. Cavalleri,
Patrick Cossette,
Chris Cotsapas,
Peter De Jonghe,
Tracy Dixon‐Salazar,
Renzo Guerrini,
Hakon Hakonarson,
Erin L. Heinzen,
Ingo Helbig,
Patrick Kwan,
Slavé Petrovski,
Sitharthan Kamalakaran,
Sanjay M. Sisodiya,
Randy Stewart,
Sarah Weckhuysen,
Dennis J. Dlugos,
Ingrid E. Scheffer,
Pasquale Striano,
Catharine Freyer,
Roland Krause,
Patrick May,
Kevin McKenna,
Brigid M. Regan,
Susannah T. Bellows,
Caitlin A. Bennett,
Esther M.C. Johns,
Alexandra Macdonald,
Hannah Shilling,
Rosemary Burgess,
Dorien Weckhuysen,
Melanie Bahlo,
Terence J. O'Brien,
Marian Todaro,
Hannah Stamberger,
Chantal Depondt,
Danielle M. Andrade,
Tara R. Sadoway,
Kelly Mo,
Heinz Krestel,
Sabina Gallati,
Savvas S. Papacostas,
Ioanna Kousiappa,
George A. Tanteles,
Katalin Štěrbová,
Markéta Vlčková,
Lucie Sedláčková,
Petra Laššuthová,
Karl Martin Klein,
Felix Rosenow,
Philipp S. Reif,
Susanne Knake,
Wolfram S. Kunz,
Gábor Zsurka,
Christian E. Elger,
Jürgen Bauer,
Michael Rademacher,
Manuela Pendziwiat,
Hiltrud Muhle,
Annika Rademacher,
Andreas Baalen,
Sarah Spiczak,
Ulrich Stephani,
Zaid Afawi,
Amos D. Korczyn,
Moien Kanaan,
Christina Canavati,
Gerhard Kurlemann,
Karen Müller‐Schlüter,
Gerhard Kluger,
Martin Häusler,
Ilan Blatt,
Johannes R. Lemke,
Ilona Krey,
Yvonne G. Weber,
Stefan Wolking,
Felicitas Becker,
Christian Hengsbach,
Sarah Rau,
Ana F. Maisch,
Bernhard J. Steinhoff,
Andreas Schulze‐Bonhage,
Susanne Schubert‐Bast,
Herbert Schreiber,
Ingo Borggräfe,
Christoph J. Schankin,
Thomas Mayer,
Rudolf Korinthenberg,
Knut Brockmann,
Dieter Dennig,
Rene Madeleyn,
Reetta Kälviäinen,
Pia Auvinen,
Anni Saarela,
Tarja Linnankivi,
Anna‐Elina Lehesjoki,
Mark I. Rees,
Seo‐Kyung Chung,
William O. Pickrell,
Robert Powell,
Natascha Schneider,
Simona Balestrini,
Sara Zagaglia,
Vera Braatz,
Anthony G. Marson,
Michael R. Johnson,
Pauls Auce,
Graeme J. Sills,
Larry W. Baum,
Pak C. Sham,
Stacey S. Cherny,
Colin H.T. Lui,
Nina Barišić,
Norman Delanty,
Colin P. Doherty,
Arif Shukralla,
Mark McCormack,
Hany El‐Naggar,
Laura Canafoglia,
Silvana Franceschetti,
Barbara Castellotti,
Tiziana Granata,
Federico Zara,
Michele Iacomino,
Francesca Madia,
Maria Stella Vari,
Maria Margherita Mancardi,
Vincenzo Salpietro,
Francesca Bisulli,
Paolo Tinuper,
Laura Licchetta,
Tommaso Pippucci,
Carlotta Stipa,
Raffaella Minardi,
Antonio Gambardella,
Angelo Labate,
Grazia Annesi,
Lorella Manna,
Monica Gagliardi,
Elena Parrini,
Davide Mei,
Annalisa Vetro,
Claudia Bianchini,
Martino Montomoli,
Viola Doccini,
Carla Marini,
Toshimitsu Suzuki,
Yushi Inoue,
Kazuhiro Yamakawa,
Birute Tumiene,
Lynette G. Sadleir,
Chontelle King,
Emily Mountier,
S. Hande Caglayan,
Mutluay Arslan,
Zuhal Yapıcı,
Uluc Yis,
Pınar Topaloglu,
Bulent Kara,
Dilsad Turkdogan,
Aslı Gundogdu‐Eken,
Nerses Bebek,
Sibel Uğur‐İşeri,
Betül Baykan,
Barış Salman,
Garen Haryanyan,
Emrah Yücesan,
Yeşim Kesim,
Çiğdem Özkara,
Annapurna Poduri,
Russell J. Buono,
Thomas N. Ferraro,
Michael R. Sperling,
Warren Lo,
Michael Privitera,
Jacqueline A. French,
Steven Schachter,
Ruben I. Kuzniecky,
Manu Hegde,
Pouya Khankhanian,
Katherine L. Helbig,
Colin A. Ellis,
(International League Against Epilepsy Consortium on Complex Epilepsies),
(Epi25 Collaborative)
Epilepsia, Volume: 62, Issue: 7, Pages: 1518 - 1527
Swansea University Author: Robert Powell
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DOI (Published version): 10.1111/epi.16922
Abstract
ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and backgr...
| Published in: | Epilepsia |
|---|---|
| ISSN: | 0013-9580 1528-1167 |
| Published: |
Wiley
2021
|
| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa60623 |
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| Abstract: |
ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy. |
|---|---|
| Keywords: |
beta power, EEG, generalized epilepsy, GGE, oscillations, PRS |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Science Foundation Ireland. Grant Numbers: 16/RC/3948, 13/CDA/2223; European Regional Development Fund; FutureNeuro industry partners; Wellcome Trust. Grant Numbers: 084730, WT066056; Epilepsy Society, UK, NIHR. Grant Number: 08-08-SCC; GIHE. Grant Numbers: NIH R01-NS-49306-01, NIH R01-NS-053998; GSCFE. Grant Number: NIH R01-NS-064154-01; NIH. Grant Number: UL1TR001070; The Children’s Hospital of Philadelphia; NHMRC. Grant Number: 1091593; The Royal Melbourne Hospital Foundation Lottery Grant; The RMH Neuroscience Foundation; European Union’s Seventh Framework Programme (FP7/2007-2013). Grant Number: 279062; Department of Health’s NIHR Biomedical Research Centers funding scheme, European Community. Grant Number: LSHM-CT2006-037315; German Research Foundation. Grant Number: SA434/4-1/4-26-1; European Science Foundation. Grant Numbers: SA434/5-1, NU50/8-1, LE1030/11-1, HE5415/3-1, RO 3396/2-1; German Federal Ministry of Education and Research, National Genome Research Network. Grant Numbers: 01GS08120, 01GS08123; The Netherlands National Epilepsy Fund. Grant Number: 04-08; Research Grants Council of the Hong Kong Special Administrative Region. Grant Numbers: HKU7623/08 M, HKU7747/ 07 M, CUHK4466/06 M; Fonds National de la Recherche Scientifique; Fondation Erasme; Université Libre de Bruxelles; NIHR Biomedical Research Centres Schem. Grant Number: P31753; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Grant Number: N01HD33348; German Ministry for Education and Research. Grant Number: 01EY1103; Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria; Helmholtz Zentrum München–German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria; Munich Center of Health Sciences; Ludwig Maximilian University, as part of LMUinnovativ |
| Issue: |
7 |
| Start Page: |
1518 |
| End Page: |
1527 |