A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern.
BACKGROUND
The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases.


OBJECTIVE
To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP.


METHODS
We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages.


RESULTS
Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance.


CONCLUSIONS
In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
Moritz F
MF
Sinner
Kimmo
K
Porthan
Peter A
PA
Noseworthy
Aki S
AS
Havulinna
Jani T
JT
Tikkanen
Martina
M
Müller-Nurasyid
Gina
G
Peloso
Sheila
S
Ulivi
Britt Maria
BM
Beckmann
A Catharina
AC
Brockhaus
Rebecca R
RR
Cooper
Paolo
P
Gasparini
Christian
C
Hengstenberg
Shih-Jen
SJ
Hwang
Annamaria
A
Iorio
M Juhani
MJ
Junttila
Norman
N
Klopp
Mika
M
Kähönen
Maarit A
MA
Laaksonen
Terho
T
Lehtimäki
Peter
P
Lichtner
Leo-Pekka
LP
Lyytikäinen
Eimo
E
Martens
Christa
C
Meisinger
Thomas
T
Meitinger
Faisal M
FM
Merchant
Markku S
MS
Nieminen
Annette
A
Peters
Arto
A
Pietilä
Siegfried
S
Perz
Lasse
L
Oikarinen
Olli
O
Raitakari
Wibke
W
Reinhard
Kaisa
K
Silander
Barbara
B
Thorand
H-Erich
HE
Wichmann
Gianfranco
G
Sinagra
Jorma
J
Viikari
Christopher J
CJ
O'Donnell
Patrick T
PT
Ellinor
Heikki V
HV
Huikuri
Stefan
S
Kääb
Christopher
C
Newton-Cheh
Veikko
V
Salomaa
D001145:Arrhythmias, Cardiac / Q000235:genetics*; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors