Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae

Abstract

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.

Figure 1

Quantile-quantile plot of PR interval association results for 338,049 autosomal SNPs under an additive genetic model. Plotted are the expected versus observed −log₁₀(p-value) before (black) and after (red) genomic control from the PR interval GWAS. The measure of overdispersion of the test statistics, λ_GC, was 1.16 before genomic control.

Figure 2

PR interval association results for 338,049 SNPs across 22 autosomes under an additive genetic model. Each dot represents one SNP. Plotted on the y-axis is −log₁₀(p-value) and on the x-axis physical position by chromosome.

Figure 3

Regional association plot for PR interval top locus on chromosome 3p. The plot covers the genomic region from 150 kb upstream of SCN5A to 300 kb downstream. Positions are from NCBI build 35 and recombination rates as estimated from HapMap phase II. SNPs are represented by diamonds and the large blue diamond is the SNP with the highest p-value. Diamond color represents correlation with the top SNP: faint red indicates weak correlation and brighter red indicates strong correlation. Recombination rate is plotted in the background and known genes in the region are shown in the bottom of the plot.

Figure 4

Linkage Disequilibrium plot showing all SNPs with p<10⁻⁵ and intervening SNPs in the genomic region of SCN5A and downstream. Values in the boxes are pairwise SNP correlations (r²); box color reflects the degree of correlation. An empty, dark box indicates complete correlation (r² = 100%) and a clear box indicates low correlation. The LD block including most of the associated SNPs was defined by the criteria of Gabriel et al as implemented in Haploview. The strongest and second strongest associated SNPs are indicated with red and blue boxes, respectively. Correlations were calculated in the 133 most distantly related Kosraeans (see Methods). Panel B shows haplotypes with all 19 SNPs in the region constructed in Haploview in which each line represents one haplotype followed by its frequency on Kosrae and the numbers above each column correspond to the number for each SNP as given in the LD plot. Panel C shows haplotypes of the same SNPs from the Asian populations CHB/JPT in HapMap rel21. Haplotypes with frequencies below 0.02 were excluded.