Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Authors:   The International League Against Epilepsy Consortium on Complex Epilepsies, 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. , Feucht 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 Aarno , 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 Eileen 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 Stefan , Yang Wanling , Zara Federico , Zimprich Fritz 
Published: December 2018

AbstractThe 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.