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. Bradfield; 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 Delanty; Chantal 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 Kaelviaeinen; Anne-Mari Kantanen; Dalia Kasperaviciute; Dorothee Kasteleijn-Nolst Trenite; Bobby P. C.  Koeleman; Wolfram S. Kunz; Patrick Kwan; Yu Lung Lau; Dick Lindhout

doi:10.1016/S1474-4422(14)70171-1

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. Bradfield, 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 Kaelviaeinen, Anne-Mari Kantanen, Dalia Kasperaviciute, Dorothee Kasteleijn-Nolst Trenite, Bobby P. C. Koeleman, Wolfram S. Kunz, Patrick Kwan, Yu Lung Lau, Dick Lindhout, ,

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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

Findings We included 8696 cases and 26157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8.71 x 10(-10), implicating SCN1A, and at 4p15.1 (p=5.44 x 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 x 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).

Original language	English
Pages (from-to)	893-903
Number of pages	11
Journal	Lancet Neurology
Volume	13
Issue number	9
DOIs	https://doi.org/10.1016/S1474-4422(14)70171-1
Publication status	Published - Sept 2014

Keywords

DE-NOVO MUTATIONS
IDIOPATHIC GENERALIZED EPILEPSY
NON-CLUSTERED PROTOCADHERIN
NEURONAL SODIUM-CHANNEL
FEBRILE SEIZURES PLUS
SUSCEPTIBILITY LOCI
RISK
SCN1A
SCHIZOPHRENIA
COMPLEX

Access to Document

10.1016/S1474-4422(14)70171-1

Cite this

Anney, R. J. L., Avbersek, A., Balding, D., Baum, L., Becker, F., Berkovic, S. F., Bradfield, 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. (2014). Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurology, 13(9), 893-903. https://doi.org/10.1016/S1474-4422(14)70171-1

@article{e011ddb512e9486f82f35e5d111c5f68,

title = "Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies",

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 pFindings We included 8696 cases and 26157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8.71 x 10(-10), implicating SCN1A, and at 4p15.1 (p=5.44 x 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 x 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).",

keywords = "DE-NOVO MUTATIONS, IDIOPATHIC GENERALIZED EPILEPSY, NON-CLUSTERED PROTOCADHERIN, NEURONAL SODIUM-CHANNEL, FEBRILE SEIZURES PLUS, SUSCEPTIBILITY LOCI, RISK, SCN1A, SCHIZOPHRENIA, COMPLEX",

author = "Anney, {Richard J. L.} and Andreja Avbersek and David Balding and Larry Baum and Felicitas Becker and Berkovic, {Samuel F.} and Bradfield, {Jonathan P.} and Brody, {Lawrence C.} and Buono, {Russell J.} and Catarino, {Claudia B.} and Cavalleri, {Gianpiero L.} and Cherny, {Stacey S.} and Krishna Chinthapalli and Coffey, {Alison J.} and Alastair Compston and Patrick Cossette and {de Haan}, Gerrit-Jan and {De Jonghe}, Peter and {de Kovel}, {Carolien G F} and Norman Delanty and Chantal Depondt and Dlugos, {Dennis J.} and Doherty, {Colin P.} and Elger, {Christian E.} and Ferraro, {Thomas N.} and Martha Feucht and Andre Franke and Jacqueline French and Verena Gaus and Goldstein, {David B.} and Hongsheng Gui and Youling Guo and Hakon Hakonarson and Kerstin Hallmann and Heinzen, {Erin L.} and Ingo Helbig and Helle Hjalgrim and Margaret Jackson and Jennifer Jamnadas-Khoda and Dieter Janz and Johnson, {Michael R.} and Reetta Kaelviaeinen and Anne-Mari Kantanen and Dalia Kasperaviciute and {Kasteleijn-Nolst Trenite}, Dorothee and Koeleman, {Bobby P. C.} and Kunz, {Wolfram S.} and Patrick Kwan and Lau, {Yu Lung} and Dick Lindhout",

year = "2014",

month = sep,

doi = "10.1016/S1474-4422(14)70171-1",

language = "English",

volume = "13",

pages = "893--903",

journal = "Lancet Neurology",

issn = "1474-4422",

publisher = "Elsevier Limited",

number = "9",

}

Anney, RJL, Avbersek, A, Balding, D, Baum, L, Becker, F, Berkovic, SF, Bradfield, JP, Brody, LC, Buono, RJ, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Cossette, P, de Haan, G-J, De Jonghe, P, de Kovel, CGF, Delanty, N, Depondt, C, Dlugos, DJ, Doherty, CP, Elger, CE, Ferraro, TN, Feucht, M, Franke, A, French, J, Gaus, V, Goldstein, DB, Gui, H, Guo, Y, Hakonarson, H, Hallmann, K, Heinzen, EL, Helbig, I, Hjalgrim, H, Jackson, M, Jamnadas-Khoda, J, Janz, D, Johnson, MR, Kaelviaeinen, R, Kantanen, A-M, Kasperaviciute, D, Kasteleijn-Nolst Trenite, D, Koeleman, BPC, Kunz, WS, Kwan, P, Lau, YL, Lindhout, D 2014, 'Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies', Lancet Neurology, vol. 13, no. 9, pp. 893-903. https://doi.org/10.1016/S1474-4422(14)70171-1

TY - JOUR

T1 - Genetic determinants of common epilepsies

T2 - a meta-analysis of genome-wide association studies

AU - Anney, Richard J. L.

AU - Avbersek, Andreja

AU - Balding, David

AU - Baum, Larry

AU - Becker, Felicitas

AU - Berkovic, Samuel F.

AU - Bradfield, 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 - Kaelviaeinen, Reetta

AU - Kantanen, Anne-Mari

AU - Kasperaviciute, Dalia

AU - Kasteleijn-Nolst Trenite, Dorothee

AU - Koeleman, Bobby P. C.

AU - Kunz, Wolfram S.

AU - Kwan, Patrick

AU - Lau, Yu Lung

AU - Lindhout, Dick

PY - 2014/9

Y1 - 2014/9

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 pFindings We included 8696 cases and 26157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8.71 x 10(-10), implicating SCN1A, and at 4p15.1 (p=5.44 x 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 x 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).

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 pFindings We included 8696 cases and 26157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8.71 x 10(-10), implicating SCN1A, and at 4p15.1 (p=5.44 x 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 x 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).

KW - DE-NOVO MUTATIONS

KW - IDIOPATHIC GENERALIZED EPILEPSY

KW - NON-CLUSTERED PROTOCADHERIN

KW - NEURONAL SODIUM-CHANNEL

KW - FEBRILE SEIZURES PLUS

KW - SUSCEPTIBILITY LOCI

KW - RISK

KW - SCN1A

KW - SCHIZOPHRENIA

KW - COMPLEX

U2 - 10.1016/S1474-4422(14)70171-1

DO - 10.1016/S1474-4422(14)70171-1

M3 - Article

SN - 1474-4422

VL - 13

SP - 893

EP - 903

JO - Lancet Neurology

JF - Lancet Neurology

IS - 9

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this