Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae.
BACKGROUND
Cardiac conduction, as assessed by electrocardiographic PR interval and QRS duration, is an important electrophysiological trait and a determinant of arrhythmia risk.


OBJECTIVE
We sought to identify common genetic determinants of these measures.


METHODS
We examined 1604 individuals from the island of Kosrae, Federated States of Micronesia, an isolated founder population. We adjusted for covariates and estimated the heritability of quantitative electrocardiographic QRS duration and PR interval and, secondarily, its subcomponents, P-wave duration and PR segment. Finally, we performed a genome-wide association study (GWAS) in a subset of 1262 individuals genotyped using the Affymetrix GeneChip Human Mapping 500K microarray.


RESULTS
The heritability of PR interval was 34% (standard error [SE] 5%, P = 4 x 10(-18)); of PR segment, 31% (SE 6%, P = 3.2 x 10(-13)); and of P-wave duration, 17% (SE 5%, P = 5.8 x 10(-6)), but the heritablility of QRS duration was only 3% (SE 4%, P = .20). Hence, GWAS was performed only for the PR interval and its subcomponents. A total of 338,049 single nucleotide polymorphisms (SNPs) passed quality filters. For the PR interval, the most significantly associated SNPs were located in and downstream of the alpha-subunit of the cardiac voltage-gated sodium channel gene SCN5A, with a 4.8 ms (SE 1.0) or 0.23 standard deviation increase in adjusted PR interval for each minor allele copy of rs7638909 (P = 1.6 x 10(-6), minor allele frequency 0.40). These SNPs were also associated with P-wave duration (P = 1.5 x 10(-4)) and PR segment (P = .01) but not with QRS duration (P > or =.22).


CONCLUSIONS
The PR interval and its subcomponents showed substantial heritability in a South Pacific islander population and were associated with common genetic variation in SCN5A.
Smith
J Gustav
JG
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Lowe
Jennifer K
JK
Kovvali
Sirisha
S
Maller
Julian B
JB
Salit
Jacqueline
J
Daly
Mark J
MJ
Stoffel
Markus
M
Altshuler
David M
DM
Friedman
Jeffrey M
JM
Breslow
Jan L
JL
Newton-Cheh
Christopher
C
D000328:Adult; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D004247:DNA / Q000235:genetics; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D008297:Male; D008849:Micronesia / Q000453:epidemiology; D009124:Muscle Proteins / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012189:Retrospective Studies; D015222:Sodium Channels / Q000235:genetics
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D004247:DNA