Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts

Abstract

Background: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

Methods and results: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

Conclusions: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

Figure 1

Manhattan plot of the association of SNPs with PR in a meta-analysis of ten African American cohorts. The x-axis represents the chromosomal position for each SNP, and the y-axis represents the −log10 P-value for association with PR, which is truncated at 1×10⁻²³.

Figure 2

Regional association plots of six loci associated with PR interval in ten African American cohorts. SNP P-values (represented by circles) at each locus are shown on the −log₁₀(P-value) scale as a function of chromosomal position. Strength of LD is indicated by the color category. Purple diamonds denotes the locus-specific primary signal. Recombination rate is plotted in the background and known genes are shown on the bottom of the plot. A) MEIS1; b) ITGA9; c) SCN5A; d) ARHGAP24; e) CAV1; f) TBX5.