Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies
Authors: Richard Anney, Andreja Avbersek, David Balding, Larry Baum, Felicitas Becker, Samuel Berkovic, Jonathan Bradfi Eld, Lawrence Brody, Russell Buono, Claudia Catarino, Gianpiero Cavalleri, Stacey Cherny, Krishna Chinthapalli, Alison Coff Ey, Alastair Compston, Patrick Cossette, Gerrit-Jan De Haan, Peter De Jonghe, Carolien F De Kovel, Norman Delanty, Chantal Depondt, Dennis Dlugos, Colin Doherty, Christian Elger, Thomas Ferraro, Martha Feucht, Andre Franke, Jacqueline French, Verena Gaus, David Goldstein, Hongsheng Gui, Youling Guo, Hakon Hakonarson, Kerstin Hallmann, Erin Heinzen, Ingo Helbig, Helle Hjalgrim, Margaret Jackson, Jennifer Jamnadas-Khoda, Dieter Janz, Michael Johnson, Reetta Kälviäinen, Anne-Mari Kantanen, Dalia Kasperavičiūte, Dorothee Kasteleijn-Nolst, Bobby Trenite, Wolfram Koeleman, Patrick Kunz, Yu Kwan, Anna-Elina Lau, Holger Lehesjoki, Costin Lerche, Wolfgang Leu, Dick Lieb, Warren Lindhout, Daniel Lo, Alberto Lowenstein, Anthony Malovini, Mark Marson, James Mccormack, Martina Mills, Rikke Moerzinger, Anne Møller, Hiltrud Molloy, Mark Muhle, Ping-Wing Newton, Markus Ng, Peter Nöthen, Terence Nürnberg, Karen O'brien, Aarno Oliver, Faith Palotie, Katharina Pangilinan, Slave Pernhorst, Michael Petrovski, Rodney Privitera, Philipp Radtke, Felix Reif, Ann-Kathrin Rosenow, Thomas Ruppert, Theresa Sander, Steven Scattergood, Christoph Schachter, Ingrid Schankin, Bettina Scheff Er, Susanne Schmitz, Pak Schoch, Sanjay Sham, David Sisodiya, Philip Smith, Doug Smith, Michael Speed, Michael Sperling, Ulrich Stephani, Pasquale Striano, Hans Stroink, Rainer Surges, Meng Tan, Neil Thomas, Marian Todaro, Anna Tostevin, Rossana Tozzi, Holger Trucks, Frank Visscher, Sarah Von Spiczak, Nicole Walley, Yvonne Weber, Zhi Wei, Christopher Whelan, Wanling Yang, Federico Zara, Fritz Affi, A-El Sfb, Mrj Sfb, G-Jdh Aa, Fzar Control, William Gallentine, Aatif Husain, Mohamad Mikati, Saurabh Sinha, Raju Yerra, Chris French, Zelko Matkovic, Steven Howell, Paul Cooper, Mark Kellett, Brendan Mclean, Marcus Reuber, Peter Cleland, Kathleen White, Peter Goulding, Richard Appleton, Mark Lawden, Basil Sharrack, Guiliano Avanzini, Ditte Kjelgaard, Oebele Brouwer, Floor Jansen, Kees Braun, Hans Carpay, Willem Arts, Paul Boon, Lenora Lehwald, Jorge Vidaurre, Pedro Weisleder, Chang-Yong Tsao, Annie Kung, Monica Islam, Emily De Los Reyes, Jennifer Mckinney, Laurel Slaughter, Bethanie Morgan-Followell, Lori Hamiwka, Deborah Terry, Molly Taylor, Sally Steward, Mary Karn, Jo Lee, Donna Kring, Sarah Borror, Karen Carter, Cathy Schumer, Guy Rouleau, Micheline Gravel, Virginia Wong, Colin Lui, Ngai Chuen, Tak-Hong Tsoi, Rhian Gwilliam
Journal: The Lancet Neurology (2014)

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).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<1·66 × 10(-8).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.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).International League Against Epilepsy and multiple governmental and philanthropic agencies.