Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.
Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Dalia
D
Kasperaviciūte
Claudia B
CB
Catarino
Erin L
EL
Heinzen
Chantal
C
Depondt
Gianpiero L
GL
Cavalleri
Luis O
LO
Caboclo
Sarah K
SK
Tate
Jenny
J
Jamnadas-Khoda
Krishna
K
Chinthapalli
Lisa M S
LM
Clayton
Kevin V
KV
Shianna
Rodney A
RA
Radtke
Mohamad A
MA
Mikati
William B
WB
Gallentine
Aatif M
AM
Husain
Saud
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Alhusaini
David
D
Leppert
Lefkos T
LT
Middleton
Rachel A
RA
Gibson
Michael R
MR
Johnson
Paul M
PM
Matthews
David
D
Hosford
Kjell
K
Heuser
Leslie
L
Amos
Marcos
M
Ortega
Dominik
D
Zumsteg
Heinz-Gregor
HG
Wieser
Bernhard J
BJ
Steinhoff
Günter
G
Krämer
Jörg
J
Hansen
Thomas
T
Dorn
Anne-Mari
AM
Kantanen
Leif
L
Gjerstad
Terhi
T
Peuralinna
Dena G
DG
Hernandez
Kai J
KJ
Eriksson
Reetta K
RK
Kälviäinen
Colin P
CP
Doherty
Nicholas W
NW
Wood
Massimo
M
Pandolfo
John S
JS
Duncan
Josemir W
JW
Sander
Norman
N
Delanty
David B
DB
Goldstein
Sanjay M
SM
Sisodiya
D004828:Epilepsies, Partial / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D038622:Internationality; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013577:Syndrome