Genetic determinants of common epilepsies: A meta-analysis of genome-wide association studies

Richard J L Anney, Andreja Avbersek, David Balding, Larry Baum, Felicitas Becker, Samuel F. Berkovic, Jonathan P. Bradfi, Lawrence C. Brody, Russell J. Buono, Claudia B. Catarino, Gianpiero L. Cavalleri, Stacey S. Cherny, Krishna Chinthapalli, Alison J. Coffey, Alastair Compston, Patrick Cossette, Gerrit Jan De Haan, Peter De Jonghe, Carolien G F De Kovel, Norman DelantyChantal Depondt, Dennis J. Dlugos, Colin P. Doherty, Christian E. Elger, Thomas N. Ferraro, Martha Feucht, Andre Franke, Jacqueline French, Verena Gaus, David B. Goldstein, Hongsheng Gui, Youling Guo, Hakon Hakonarson, Kerstin Hallmann, Erin L. Heinzen, Ingo Helbig, Helle Hjalgrim, Margaret Jackson, Jennifer Jamnadas-Khoda, Dieter Janz, Michael R. Johnson, Reetta Kalviainen, Anne Mari Kantanen, Dalia Kasperaviciute, Dorothee Kasteleijn Nolst Trenite, Bobby P C Koeleman, Wolfram S. Kunz, Patrick Kwan, Yu Lung Lau, Anna Elina Lehesjoki, Holger Lerche, Costin Leu, Wolfgang Lieb, Dick Lindhout, Warren Lo, Daniel H. Lowenstein, Alberto Malovini, Anthony G. Marson, Mark McCormack, James L. Mills, Martina Moerzinger, Rikke S. Moller, Anne M. Molloy, Hiltrud Muhle, Mark Newton, Ping Wing Ng, Markus M. Nothen, Peter Nurnberg, Terence J. OBrien, Karen L. Oliver, Aarno Palotie, Faith Pangilinan, Katharina Pernhorst, Slave Petrovski, Michael Privitera, Rodney Radtke, Philipp S. Reif, Felix Rosenow, Ann Kathrin Ruppert, Thomas Sander, Theresa Scattergood, Steven Schachter, Christoph Schankin, Ingrid E. Scheffer, Bettina Schmitz, Susanne Schoch, Pak C. Sham, Sanjay Sisodiya, David F. Smith, Philip E. Smith, Doug Speed, Michael R. Sperling, Michael Steffens, Ulrich Stephani, Pasquale Striano, Hans Stroink, Rainer Surges, K. Meng Tan, G. Neil Thomas, Marian Todaro, Anna Tostevin, Rossana Tozzi, Holger Trucks, Frank Visscher, Sarah von Spiczak, Nicole M. Walley, Yvonne G. Weber, Zhi Wei, Christopher Whelan, Wanling Yang, Federico Zara, Fritz Zimprich

Research output: Contribution to journalArticle

Abstract

Background: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods: We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p-8. Findings: We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10-10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10-9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10-9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation: This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes). Funding: International League Against Epilepsy and multiple governmental and philanthropic agencies.

Original languageEnglish
Pages (from-to)893-903
Number of pages11
JournalThe Lancet Neurology
Volume13
Issue number9
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Clinical Neurology

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    Anney, R. J. L., Avbersek, A., Balding, D., Baum, L., Becker, F., Berkovic, S. F., Bradfi, J. P., Brody, L. C., Buono, R. J., Catarino, C. B., Cavalleri, G. L., Cherny, S. S., Chinthapalli, K., Coffey, A. J., Compston, A., Cossette, P., De Haan, G. J., De Jonghe, P., De Kovel, C. G. F., ... Zimprich, F. (2014). Genetic determinants of common epilepsies: A meta-analysis of genome-wide association studies. The Lancet Neurology, 13(9), 893-903. https://doi.org/10.1016/S1474-4422(14)70171-1