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

2014; Elsevier BV; Volume: 13; Issue: 9 Linguagem: Inglês

10.1016/s1474-4422(14)70171-1

1474-4465

Richard Anney, Andreja Avberšek, David J. Balding, Larry Baum, Felicitas Becker, Samuel F. Berkovic, Jonathan Bradfi Eld, Lawrence C. Brody, Russell J. Buono, Claudia B. Catarino, Gianpiero L. Cavalleri, Stacey S. Cherny, Krishna Chinthapalli, Alison Coff Ey, Alastair Compston, Patrick Cossette, Gerrit‐Jan de Haan, Peter De Jonghe, Carolien G. F. de Kovel, Norman Delanty, Chantal Depondt, Dennis Dlugos, Colin P. Doherty, Christian E. Elger, Thomas N. Ferraro, Martha Feucht, Andre Franke, Jacqueline A. French, Verena Gaus, David B. Goldstein, Hongsheng Gui, Youling Guo, Hákon Hákonarson, Kerstin Hallmann, Erin L. Heinzen, Ingo Helbig, Helle Hjalgrim, Margaret Jackson, Jennifer Jamnadas-Khoda, Diéter Janz, Michael R. Johnson, Reetta Kälviäinen, Anne-Mari Kantanen, Dalia Kasperavičiūtė, Dorothee Kasteleijn-Nolst, Bobby Trenite, Wolfram Koeleman, Wolfram S. Kunz, Patrick Kwan, Anna-Elina Lau, Holger Lehesjoki, Costin Lerche, Costin Leu, Dick Lieb, Dick Lindhout, Daniel Lo, Alberto Lowenstein, Alberto Malovini, Anthony G Marson, Mark McCormack, James L. Mills, Rikke Moerzinger, Rikke S. Møller, Anne M. Molloy, Mark Muhle, Ping-Wing Newton, Markus Ng, Markus M. Nöthen, Terence Nürnberg, Terence J. O’Brien, Karen Oliver, Aarno Palotie, Katharina Pangilinan, Slave Pernhorst, Slavé 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, S. W. Simon Sham, David Sisodiya, Phil E M Smith, Doug W. Smith, Michael P. Speed, Michael R. Sperling, Ulrich Stephani, Pasquale Striano, Hans Stroink, Rainer Surges, Meng Tan, G. Neil Thomas, Marian Todaro, Anna Tostevin, Rossana Tozzi, Holger Trucks, Frank Visscher, Sarah von Spiczak, Sophie Nicole, Yvonne G. Weber, Zhi Wei, Christopher D. Whelan, Wanling Yang, Federico Zara, Fritz Affi, A-El Sfb, Mrj Sfb, G-Jdh Aa, Fzar Control, William Gallentine, Aatif M. Husain, Mohamad A. Mikati, Saurabh Sinha, Raju Yerra, Chris French, Zelko Matkovic, Steven Howell, Paul Cooper, Mark Kellett, Brendan McLean, M.D. Reuber, Peter Cleland, Kathleen M. White, Peter Goulding, Richard Appleton, Mark Lawden, Basil Sharrack, Guiliano Avanzini, Ditte B. Kjelgaard, Oebele F. Brouwer, Floor E. Jansen, Kees P. J. Braun, Hans A. Carpay, Willem F. Arts, Paul Boon, Lenora Lehwald, Jorge Vidaurre, Pedro Weisleder, Chang‐Yong Tsao, Annie W.C. Kung, Monica P. Islam, Emily de los Reyes, Jennifer L. McKinney, Laurel Slaughter, Bethanie Morgan-Followell, L Hamiwka, Deborah J. Terry, Molly A. Taylor, Sally Steward, MARY N. KARN, J.J. Lee, Donna Kring, Sarah Borror, Kelly Erikson Carter, Cathy Schumer, Guy A. Rouleau, Micheline Gravel, Virginia Wong, Colin H. T. Lui, Ngai Chuen, Tak‐Hong Tsoi, Rhian Gwilliam,

Epilepsy research and treatment

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.