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.
Kasperaviciūte
Dalia
D
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Catarino
Claudia B
CB
Heinzen
Erin L
EL
Depondt
Chantal
C
Cavalleri
Gianpiero L
GL
Caboclo
Luis O
LO
Tate
Sarah K
SK
Jamnadas-Khoda
Jenny
J
Chinthapalli
Krishna
K
Clayton
Lisa M S
LM
Shianna
Kevin V
KV
Radtke
Rodney A
RA
Mikati
Mohamad A
MA
Gallentine
William B
WB
Husain
Aatif M
AM
Alhusaini
Saud
S
Leppert
David
D
Middleton
Lefkos T
LT
Gibson
Rachel A
RA
Johnson
Michael R
MR
Matthews
Paul M
PM
Hosford
David
D
Heuser
Kjell
K
Amos
Leslie
L
Ortega
Marcos
M
Zumsteg
Dominik
D
Wieser
Heinz-Gregor
HG
Steinhoff
Bernhard J
BJ
Krämer
Günter
G
Hansen
Jörg
J
Dorn
Thomas
T
Kantanen
Anne-Mari
AM
Gjerstad
Leif
L
Peuralinna
Terhi
T
Hernandez
Dena G
DG
Eriksson
Kai J
KJ
Kälviäinen
Reetta K
RK
Doherty
Colin P
CP
Wood
Nicholas W
NW
Pandolfo
Massimo
M
Duncan
John S
JS
Sander
Josemir W
JW
Delanty
Norman
N
Goldstein
David B
DB
Sisodiya
Sanjay M
SM
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