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 Delanty & 92 others 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 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

111 Citations (Scopus)

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

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Epilepsy
Generalized Epilepsy
Partial Epilepsy
Genome
Inborn Genetic Diseases
Nervous System Diseases
Quality Control
Sample Size
Single Nucleotide Polymorphism
Linear Models

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Anney, R. J. L., Avbersek, A., Balding, D., Baum, L., Becker, F., Berkovic, S. 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

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

In: The Lancet Neurology, Vol. 13, No. 9, 2014, p. 893-903.

Research output: Contribution to journalArticle

Anney, RJL, Avbersek, A, Balding, D, Baum, L, Becker, F, Berkovic, SF, Bradfi, JP, Brody, LC, Buono, RJ, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Cossette, P, De Haan, GJ, 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, Kalviainen, R, Kantanen, AM, Kasperaviciute, D, Trenite, DKN, Koeleman, BPC, Kunz, WS, Kwan, P, Lau, YL, Lehesjoki, AE, Lerche, H, Leu, C, Lieb, W, Lindhout, D, Lo, W, Lowenstein, DH, Malovini, A, Marson, AG, McCormack, M, Mills, JL, Moerzinger, M, Moller, RS, Molloy, AM, Muhle, H, Newton, M, Ng, PW, Nothen, MM, Nurnberg, P, OBrien, TJ, Oliver, KL, Palotie, A, Pangilinan, F, Pernhorst, K, Petrovski, S, Privitera, M, Radtke, R, Reif, PS, Rosenow, F, Ruppert, AK, Sander, T, Scattergood, T, Schachter, S, Schankin, C, Scheffer, IE, Schmitz, B, Schoch, S, Sham, PC, Sisodiya, S, Smith, DF, Smith, PE, Speed, D, Sperling, MR, Steffens, M, Stephani, U, Striano, P, Stroink, H, Surges, R, Tan, KM, Thomas, GN, Todaro, M, Tostevin, A, Tozzi, R, Trucks, H, Visscher, F, Spiczak, SV, Walley, NM, Weber, YG, Wei, Z, Whelan, C, Yang, W, Zara, F & Zimprich, F 2014, 'Genetic determinants of common epilepsies: A meta-analysis of genome-wide association studies', The Lancet Neurology, vol. 13, no. 9, pp. 893-903. https://doi.org/10.1016/S1474-4422(14)70171-1
Anney, Richard J L ; Avbersek, Andreja ; Balding, David ; Baum, Larry ; Becker, Felicitas ; Berkovic, Samuel F. ; Bradfi, Jonathan P. ; Brody, Lawrence C. ; Buono, Russell J. ; Catarino, Claudia B. ; Cavalleri, Gianpiero L. ; Cherny, Stacey S. ; Chinthapalli, Krishna ; Coffey, Alison J. ; Compston, Alastair ; Cossette, Patrick ; De Haan, Gerrit Jan ; De Jonghe, Peter ; De Kovel, Carolien G F ; Delanty, Norman ; Depondt, Chantal ; Dlugos, Dennis J. ; Doherty, Colin P. ; Elger, Christian E. ; Ferraro, Thomas N. ; Feucht, Martha ; Franke, Andre ; French, Jacqueline ; Gaus, Verena ; Goldstein, David B. ; Gui, Hongsheng ; Guo, Youling ; Hakonarson, Hakon ; Hallmann, Kerstin ; Heinzen, Erin L. ; Helbig, Ingo ; Hjalgrim, Helle ; Jackson, Margaret ; Jamnadas-Khoda, Jennifer ; Janz, Dieter ; Johnson, Michael R. ; Kalviainen, Reetta ; Kantanen, Anne Mari ; Kasperaviciute, Dalia ; Trenite, Dorothee Kasteleijn Nolst ; Koeleman, Bobby P C ; Kunz, Wolfram S. ; Kwan, Patrick ; Lau, Yu Lung ; Lehesjoki, Anna Elina ; Lerche, Holger ; Leu, Costin ; Lieb, Wolfgang ; Lindhout, Dick ; Lo, Warren ; Lowenstein, Daniel H. ; Malovini, Alberto ; Marson, Anthony G. ; McCormack, Mark ; Mills, James L. ; Moerzinger, Martina ; Moller, Rikke S. ; Molloy, Anne M. ; Muhle, Hiltrud ; Newton, Mark ; Ng, Ping Wing ; Nothen, Markus M. ; Nurnberg, Peter ; OBrien, Terence J. ; Oliver, Karen L. ; Palotie, Aarno ; Pangilinan, Faith ; Pernhorst, Katharina ; Petrovski, Slave ; Privitera, Michael ; Radtke, Rodney ; Reif, Philipp S. ; Rosenow, Felix ; Ruppert, Ann Kathrin ; Sander, Thomas ; Scattergood, Theresa ; Schachter, Steven ; Schankin, Christoph ; Scheffer, Ingrid E. ; Schmitz, Bettina ; Schoch, Susanne ; Sham, Pak C. ; Sisodiya, Sanjay ; Smith, David F. ; Smith, Philip E. ; Speed, Doug ; Sperling, Michael R. ; Steffens, Michael ; Stephani, Ulrich ; Striano, Pasquale ; Stroink, Hans ; Surges, Rainer ; Tan, K. Meng ; Thomas, G. Neil ; Todaro, Marian ; Tostevin, Anna ; Tozzi, Rossana ; Trucks, Holger ; Visscher, Frank ; Spiczak, Sarah von ; Walley, Nicole M. ; Weber, Yvonne G. ; Wei, Zhi ; Whelan, Christopher ; Yang, Wanling ; Zara, Federico ; Zimprich, Fritz. / Genetic determinants of common epilepsies : A meta-analysis of genome-wide association studies. In: The Lancet Neurology. 2014 ; Vol. 13, No. 9. pp. 893-903.
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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 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.",
author = "Anney, {Richard J L} and Andreja Avbersek and David Balding and Larry Baum and Felicitas Becker and Berkovic, {Samuel F.} and Bradfi, {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 Kalviainen and Kantanen, {Anne Mari} and Dalia Kasperaviciute and Trenite, {Dorothee Kasteleijn Nolst} and Koeleman, {Bobby P C} and Kunz, {Wolfram S.} and Patrick Kwan and Lau, {Yu Lung} and Lehesjoki, {Anna Elina} and Holger Lerche and Costin Leu and Wolfgang Lieb and Dick Lindhout and Warren Lo and Lowenstein, {Daniel H.} and Alberto Malovini and Marson, {Anthony G.} and Mark McCormack and Mills, {James L.} and Martina Moerzinger and Moller, {Rikke S.} and Molloy, {Anne M.} and Hiltrud Muhle and Mark Newton and Ng, {Ping Wing} and Nothen, {Markus M.} and Peter Nurnberg and OBrien, {Terence J.} and Oliver, {Karen L.} and Aarno Palotie and Faith Pangilinan and Katharina Pernhorst and Slave Petrovski and Michael Privitera and Rodney Radtke and Reif, {Philipp S.} and Felix Rosenow and Ruppert, {Ann Kathrin} and Thomas Sander and Theresa Scattergood and Steven Schachter and Christoph Schankin and Scheffer, {Ingrid E.} and Bettina Schmitz and Susanne Schoch and Sham, {Pak C.} and Sanjay Sisodiya and Smith, {David F.} and Smith, {Philip E.} and Doug Speed and Sperling, {Michael R.} and Michael Steffens and Ulrich Stephani and Pasquale Striano and Hans Stroink and Rainer Surges and Tan, {K. Meng} and Thomas, {G. Neil} and Marian Todaro and Anna Tostevin and Rossana Tozzi and Holger Trucks and Frank Visscher and Spiczak, {Sarah von} and Walley, {Nicole M.} and Weber, {Yvonne G.} and Zhi Wei and Christopher Whelan and Wanling Yang and Federico Zara and Fritz Zimprich",
year = "2014",
doi = "10.1016/S1474-4422(14)70171-1",
language = "English",
volume = "13",
pages = "893--903",
journal = "The Lancet Neurology",
issn = "1474-4422",
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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 - 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 - Lehesjoki, Anna Elina

AU - Lerche, Holger

AU - Leu, Costin

AU - Lieb, Wolfgang

AU - Lindhout, Dick

AU - Lo, Warren

AU - Lowenstein, Daniel H.

AU - Malovini, Alberto

AU - Marson, Anthony G.

AU - McCormack, Mark

AU - Mills, James L.

AU - Moerzinger, Martina

AU - Moller, Rikke S.

AU - Molloy, Anne M.

AU - Muhle, Hiltrud

AU - Newton, Mark

AU - Ng, Ping Wing

AU - Nothen, Markus M.

AU - Nurnberg, Peter

AU - OBrien, Terence J.

AU - Oliver, Karen L.

AU - Palotie, Aarno

AU - Pangilinan, Faith

AU - Pernhorst, Katharina

AU - Petrovski, Slave

AU - Privitera, Michael

AU - Radtke, Rodney

AU - Reif, Philipp S.

AU - Rosenow, Felix

AU - Ruppert, Ann Kathrin

AU - Sander, Thomas

AU - Scattergood, Theresa

AU - Schachter, Steven

AU - Schankin, Christoph

AU - Scheffer, Ingrid E.

AU - Schmitz, Bettina

AU - Schoch, Susanne

AU - Sham, Pak C.

AU - Sisodiya, Sanjay

AU - Smith, David F.

AU - Smith, Philip E.

AU - Speed, Doug

AU - Sperling, Michael R.

AU - Steffens, Michael

AU - Stephani, Ulrich

AU - Striano, Pasquale

AU - Stroink, Hans

AU - Surges, Rainer

AU - Tan, K. Meng

AU - Thomas, G. Neil

AU - Todaro, Marian

AU - Tostevin, Anna

AU - Tozzi, Rossana

AU - Trucks, Holger

AU - Visscher, Frank

AU - Spiczak, Sarah von

AU - Walley, Nicole M.

AU - Weber, Yvonne G.

AU - Wei, Zhi

AU - Whelan, Christopher

AU - Yang, Wanling

AU - Zara, Federico

AU - Zimprich, Fritz

PY - 2014

Y1 - 2014

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-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-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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