Document Type
Article
Publication Date
12-10-2018
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.
Recommended Citation
Abou-Khalil, Bassel; Auce, Pauls; Avbersek, Andreja; Bahlo, Melanie; Balding, David J.; Bast, Thomas; Baum, Larry; Becker, Albert J.; Becker, Felicitas; Berghuis, Bianca; Berkovic, Samuel F.; Boysen, Katja E.; Bradfield, Jonathan P.; Brody, Lawrence C.; Buono, Russell J.; Campbell, Ellen; Cascino, Gregory D.; Catarino, Claudia B.; Cavalleri, Gianpiero L.; Cherny, Stacey S.; Chinthapalli, Krishna; Coffey, Alison J.; Compston, Alastair; Coppola, Antonietta; Cossette, Patrick; Craig, John J.; de Haan, Gerrit-Jan; De Jonghe, Peter; de Kovel, Carolien G.F.; Delanty, Norman; Depondt, Chantal; Devinsky, Orrin; Dlugos, Dennis J.; Doherty, Colin P.; Elger, Christian E.; Eriksson, Johan G.; Ferraro, Thomas N.; Feuch, Martha; Francis, Ben; Franke, Andre; French, Jacqueline A.; Freytag, Saskia; Gaus, Verena; Geller, Eric B.; Gieger, Christian; Glauser, Tracy; Glynn, Simon; Goldstein, David B.; Gui, Hongsheng; Guo, Youling; Haas, Kevin F.; Hakonarson, Hakon; Hallmann, Kerstin; Haut, Sheryl; Heinzen, Erin L.; Helbig, Ingo; Hengsbach, Christian; Hjalgrim, Helle; Iacomino, Michele; Ingason, Andrés; Jamnadas-Khoda, Jennifer; Johnson, Michael R.; Kälviäinen, Reetta; Kantanen, Anne-Mari; Kasperavičiūte, Dalia; Kasteleijn-Nolst Trenite, Dorothee; Kirsch, Heidi E.; Knowlton, Robert C.; Koeleman, Bobby P.C.; Krause, Roland; Krenn, Martin; Kunz, Wolfram S.; Kuzniecky, Ruben; Kwan, Patrick; Lal, Dennis; Lau, Yu-Lung; Lehesjoki, Anna-Elina; Lerche, Holger; Leu, Costin; Lieb, Wolfgang; Lindhout, Dick; Lo, Warren D.; Lopes-Cendes, Iscia; Lowenstein, Daniel H.; Malovini, Alberto; Marson, Anthony G.; Mayer, Thomas; McCormack, Mark; Mills, James L.; Mirza, Nasir; Moerzinger, Martina; Møller, Rikke S.; Molloy, Anne M.; Muhle, Hiltrud; Newton, Mark; Ng, Ping-Wing; Nöthen, Markus M.; Nürnberg, Peter; O’Brien, Terence J.; Oliver, Karen L.; Palotie, Palotie; Pangilinan, Faith; Peter, Sarah; Petrovski, Slavé; Poduri, Annapurna; Privitera, Michael; Radtke, Rodney; Rau, Sarah; Reif, Philipp S.; Reinthaler, Eva M.; Rosenow, Felix; Sander, Josemir W.; Sander, Thomas; Scattergood, Theresa; Schachter, Steven C.; Schankin, Christoph J.; Scheffer, Ingrid E.; Schmitz, Bettina; Schoch, Susanne; Sham, Pak C.; Shih, Jerry J.; Sills, Graeme J.; Sisodiya, Sanjay M.; Slattery, Lisa; Smith, Alexander; Smith, David F.; Smith, Michael C.; Smith, Philip E.; Sonsma, Anja C.M.; Speed, Doug; Sperling, Michael R.; Steinhoff, Bernhard J.; Stephani, Ulrich; Stevelink, Remi; Strauch, Konstantin; Striano, Pasquale; Stroink, Hans; Surges, Rainer; Tan, K. Meng; Thio, Liu Lin; Thomas, G. Neil; Todaro, Marian; Tozzi, Rossana; Vari, Maria S.; Vining, Ellen P.G.; Visscher, Frank; von Spiczak, Sarah; Walley, Nicole M.; Weber, Yvonne G.; Wei, Zhi; Weisenberg, Judith; Whelan, Christopher D.; Widdess-Walsh, Peter; Wolff, Markus; Wolking, Wolking; Yang, Wanling; Zara, Federico; and Zimprich, Fritz, "Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies." (2018). Department of Neurology Faculty Papers. Paper 174.
https://jdc.jefferson.edu/neurologyfp/174
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
30531953
Language
English
Comments
This article has been peer reviewed. It is the author’s final published version in Nature Communications, Volume 9, Issue 1, December 2018, Article number 5269.
The published version is available at https://doi.org/10.1038/s41467-018-07524-z. Copyright © Abou-Khalil et al.