Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The International League Against Epilepsy Consortium on Complex Epilepsies

doi:10.1038/s41467-018-07524-z

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The International League Against Epilepsy Consortium on Complex Epilepsies

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

285 Scopus citations

Abstract

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

Original language	English
Article number	5269
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07524-z
State	Published - Dec 1 2018

Access to Document

10.1038/s41467-018-07524-z

Cite this

@article{b8b70b57bd78462898acd6725eb6ee06,

title = "Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies",

abstract = "The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.",

author = "{The International League Against Epilepsy Consortium on Complex Epilepsies} and Bassel Abou-Khalil and Pauls Auce and Andreja Avbersek and Melanie Bahlo and Balding, {David J.} and Thomas Bast and Larry Baum and Becker, {Albert J.} and Felicitas Becker and Bianca Berghuis and Berkovic, {Samuel F.} and Boysen, {Katja E.} and Bradfield, {Jonathan P.} and Brody, {Lawrence C.} and Buono, {Russell J.} and Ellen Campbell and Cascino, {Gregory D.} and Catarino, {Claudia B.} and Cavalleri, {Gianpiero L.} and Cherny, {Stacey S.} and Krishna Chinthapalli and Coffey, {Alison J.} and Alastair Compston and Antonietta Coppola and Patrick Cossette and Craig, {John J.} and {de Haan}, {Gerrit Jan} and {De Jonghe}, Peter and {de Kovel}, {Carolien G.F.} and Norman Delanty and Chantal Depondt and Orrin Devinsky and Dlugos, {Dennis J.} and Doherty, {Colin P.} and Elger, {Christian E.} and Eriksson, {Johan G.} and Ferraro, {Thomas N.} and Martha Feucht and Ben Francis and Andre Franke and French, {Jacqueline A.} and Saskia Freytag and Verena Gaus and Geller, {Eric B.} and Christian Gieger and Tracy Glauser and Simon Glynn and Goldstein, {David B.} and Hongsheng Gui and Youling Guo and Haas, {Kevin F.} and Hakon Hakonarson and Kerstin Hallmann and Sheryl Haut and Heinzen, {Erin L.} and Ingo Helbig and Christian Hengsbach and Helle Hjalgrim and Michele Iacomino and Andr{\'e}s Ingason and Jennifer Jamnadas-Khoda and Johnson, {Michael R.} and Reetta K{\"a}lvi{\"a}inen and Kantanen, {Anne Mari} and Dalia Kasperavi{\v c}iūte and Dorothee Kasteleijn-Nolst Trenite and Kirsch, {Heidi E.} and Knowlton, {Robert C.} and Koeleman, {Bobby P.C.} and Roland Krause and Martin Krenn and Kunz, {Wolfram S.} and Ruben Kuzniecky and Patrick Kwan and Dennis Lal and Lau, {Yu Lung} and Lehesjoki, {Anna Elina} and Holger Lerche and Costin Leu and Wolfgang Lieb and Dick Lindhout and Lo, {Warren D.} and Iscia Lopes-Cendes and Lowenstein, {Daniel H.} and Alberto Malovini and Marson, {Anthony G.} and Thomas Mayer and Mark McCormack and Mills, {James L.} and Nasir Mirza and Martina Moerzinger and M{\o}ller, {Rikke S.} and Molloy, {Anne M.} and Hiltrud Muhle and Mark Newton and Ng, {Ping Wing} and N{\"o}then, {Markus M.} and Peter N{\"u}rnberg and O{\textquoteright}Brien, {Terence J.} and Oliver, {Karen L.} and Aarno Palotie and Faith Pangilinan and Sarah Peter and Slav{\'e} Petrovski and Annapurna Poduri and Michael Privitera and Rodney Radtke and Sarah Rau and Reif, {Philipp S.} and Reinthaler, {Eva M.} and Felix Rosenow and Sander, {Josemir W.} and Thomas Sander and Theresa Scattergood and Schachter, {Steven C.} and Schankin, {Christoph J.} and Scheffer, {Ingrid E.} and Bettina Schmitz and Susanne Schoch and Sham, {Pak C.} and Shih, {Jerry J.} and Sills, {Graeme J.} and Sisodiya, {Sanjay M.} and Lisa Slattery and Alexander Smith and Smith, {David F.} and Smith, {Michael C.} and Smith, {Philip E.} and Sonsma, {Anja C.M.} and Doug Speed and Sperling, {Michael R.} and Steinhoff, {Bernhard J.} and Ulrich Stephani and Remi Stevelink and Konstantin Strauch and Pasquale Striano and Hans Stroink and Rainer Surges and Tan, {K. Meng} and Thio, {Liu Lin} and Thomas, {G. Neil} and Marian Todaro and Rossana Tozzi and Vari, {Maria S.} and Vining, {Eileen P.G.} and Frank Visscher and {von Spiczak}, Sarah and Walley, {Nicole M.} and Weber, {Yvonne G.} and Zhi Wei and Judith Weisenberg and Whelan, {Christopher D.} and Peter Widdess-Walsh and Markus Wolff and Stefan Wolking and Wanling Yang and Federico Zara and Fritz Zimprich",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07524-z",

language = "English",

volume = "9",

journal = "Nature communications",

issn = "2041-1723",

number = "1",

}

TY - JOUR

T1 - Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

AU - The International League Against Epilepsy Consortium on Complex Epilepsies

AU - Abou-Khalil, Bassel

AU - Auce, Pauls

AU - Avbersek, Andreja

AU - Bahlo, Melanie

AU - Balding, David J.

AU - Bast, Thomas

AU - Baum, Larry

AU - Becker, Albert J.

AU - Becker, Felicitas

AU - Berghuis, Bianca

AU - Berkovic, Samuel F.

AU - Boysen, Katja E.

AU - Bradfield, Jonathan P.

AU - Brody, Lawrence C.

AU - Buono, Russell J.

AU - Campbell, Ellen

AU - Cascino, Gregory D.

AU - Catarino, Claudia B.

AU - Cavalleri, Gianpiero L.

AU - Cherny, Stacey S.

AU - Chinthapalli, Krishna

AU - Coffey, Alison J.

AU - Compston, Alastair

AU - Coppola, Antonietta

AU - Cossette, Patrick

AU - Craig, John J.

AU - de Haan, Gerrit Jan

AU - De Jonghe, Peter

AU - de Kovel, Carolien G.F.

AU - Delanty, Norman

AU - Depondt, Chantal

AU - Devinsky, Orrin

AU - Dlugos, Dennis J.

AU - Doherty, Colin P.

AU - Elger, Christian E.

AU - Eriksson, Johan G.

AU - Ferraro, Thomas N.

AU - Feucht, Martha

AU - Francis, Ben

AU - Franke, Andre

AU - French, Jacqueline A.

AU - Freytag, Saskia

AU - Gaus, Verena

AU - Geller, Eric B.

AU - Gieger, Christian

AU - Glauser, Tracy

AU - Glynn, Simon

AU - Goldstein, David B.

AU - Gui, Hongsheng

AU - Guo, Youling

AU - Haas, Kevin F.

AU - Hakonarson, Hakon

AU - Hallmann, Kerstin

AU - Haut, Sheryl

AU - Heinzen, Erin L.

AU - Helbig, Ingo

AU - Hengsbach, Christian

AU - Hjalgrim, Helle

AU - Iacomino, Michele

AU - Ingason, Andrés

AU - Jamnadas-Khoda, Jennifer

AU - Johnson, Michael R.

AU - Kälviäinen, Reetta

AU - Kantanen, Anne Mari

AU - Kasperavičiūte, Dalia

AU - Kasteleijn-Nolst Trenite, Dorothee

AU - Kirsch, Heidi E.

AU - Knowlton, Robert C.

AU - Koeleman, Bobby P.C.

AU - Krause, Roland

AU - Krenn, Martin

AU - Kunz, Wolfram S.

AU - Kuzniecky, Ruben

AU - Kwan, Patrick

AU - Lal, Dennis

AU - Lau, Yu Lung

AU - Lehesjoki, Anna Elina

AU - Lerche, Holger

AU - Leu, Costin

AU - Lieb, Wolfgang

AU - Lindhout, Dick

AU - Lo, Warren D.

AU - Lopes-Cendes, Iscia

AU - Lowenstein, Daniel H.

AU - Malovini, Alberto

AU - Marson, Anthony G.

AU - Mayer, Thomas

AU - McCormack, Mark

AU - Mills, James L.

AU - Mirza, Nasir

AU - Moerzinger, Martina

AU - Møller, Rikke S.

AU - Molloy, Anne M.

AU - Muhle, Hiltrud

AU - Newton, Mark

AU - Ng, Ping Wing

AU - Nöthen, Markus M.

AU - Nürnberg, Peter

AU - O’Brien, Terence J.

AU - Oliver, Karen L.

AU - Palotie, Aarno

AU - Pangilinan, Faith

AU - Peter, Sarah

AU - Petrovski, Slavé

AU - Poduri, Annapurna

AU - Privitera, Michael

AU - Radtke, Rodney

AU - Rau, Sarah

AU - Reif, Philipp S.

AU - Reinthaler, Eva M.

AU - Rosenow, Felix

AU - Sander, Josemir W.

AU - Sander, Thomas

AU - Scattergood, Theresa

AU - Schachter, Steven C.

AU - Schankin, Christoph J.

AU - Scheffer, Ingrid E.

AU - Schmitz, Bettina

AU - Schoch, Susanne

AU - Sham, Pak C.

AU - Shih, Jerry J.

AU - Sills, Graeme J.

AU - Sisodiya, Sanjay M.

AU - Slattery, Lisa

AU - Smith, Alexander

AU - Smith, David F.

AU - Smith, Michael C.

AU - Smith, Philip E.

AU - Sonsma, Anja C.M.

AU - Speed, Doug

AU - Sperling, Michael R.

AU - Steinhoff, Bernhard J.

AU - Stephani, Ulrich

AU - Stevelink, Remi

AU - Strauch, Konstantin

AU - Striano, Pasquale

AU - Stroink, Hans

AU - Surges, Rainer

AU - Tan, K. Meng

AU - Thio, Liu Lin

AU - Thomas, G. Neil

AU - Todaro, Marian

AU - Tozzi, Rossana

AU - Vari, Maria S.

AU - Vining, Eileen P.G.

AU - Visscher, Frank

AU - von Spiczak, Sarah

AU - Walley, Nicole M.

AU - Weber, Yvonne G.

AU - Wei, Zhi

AU - Weisenberg, Judith

AU - Whelan, Christopher D.

AU - Widdess-Walsh, Peter

AU - Wolff, Markus

AU - Wolking, Stefan

AU - Yang, Wanling

AU - Zara, Federico

AU - Zimprich, Fritz

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

AB - The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

UR - http://www.scopus.com/inward/record.url?scp=85136267598&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07524-z

DO - 10.1038/s41467-018-07524-z

M3 - Article

C2 - 30531953

AN - SCOPUS:85136267598

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5269

ER -

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Abstract

Access to Document

Other files and links

Fingerprint

Cite this