TY - JOUR
T1 - Genetic determinants of common epilepsies
T2 - A meta-analysis of genome-wide association studies
AU - International League Against Epilepsy Consortium on Complex Epilepsies
AU - The KORA study group
AU - Anney, Richard J.L.
AU - Avbersek, Andreja
AU - Balding, David
AU - Baum, Larry
AU - Becker, Felicitas
AU - Berkovic, Samuel F.
AU - Bradfi, Jonathan P.
AU - Brody, Lawrence C.
AU - Buono, Russell J.
AU - Catarino, Claudia B.
AU - Cavalleri, Gianpiero L.
AU - Cherny, Stacey S.
AU - Chinthapalli, Krishna
AU - Coffey, Alison J.
AU - Compston, Alastair
AU - Cossette, Patrick
AU - De Haan, Gerrit Jan
AU - De Jonghe, Peter
AU - De Kovel, Carolien G.F.
AU - Delanty, Norman
AU - Depondt, Chantal
AU - Dlugos, Dennis J.
AU - Doherty, Colin P.
AU - Elger, Christian E.
AU - Ferraro, Thomas N.
AU - Feucht, Martha
AU - Franke, Andre
AU - French, Jacqueline
AU - Gaus, Verena
AU - Goldstein, David B.
AU - Gui, Hongsheng
AU - Guo, Youling
AU - Hakonarson, Hakon
AU - Hallmann, Kerstin
AU - Heinzen, Erin L.
AU - Helbig, Ingo
AU - Hjalgrim, Helle
AU - Jackson, Margaret
AU - Jamnadas-Khoda, Jennifer
AU - Janz, Dieter
AU - Johnson, Michael R.
AU - Kalviainen, Reetta
AU - Kantanen, Anne Mari
AU - Kasperaviciute, Dalia
AU - Trenite, Dorothee Kasteleijn Nolst
AU - Koeleman, Bobby P.C.
AU - Kunz, Wolfram S.
AU - Kwan, Patrick
AU - Lau, Yu Lung
AU - Wei, Zhi
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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<1·66 × 10-8. 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.
AB - 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<1·66 × 10-8. 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.
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U2 - 10.1016/S1474-4422(14)70171-1
DO - 10.1016/S1474-4422(14)70171-1
M3 - Article
C2 - 25087078
SN - 1474-4422
VL - 13
SP - 893
EP - 903
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 9
ER -