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Genome-wide association studies of the PR interval in African Americans.

Smith JG, Magnani JW, Palmer C, Meng YA, Soliman EZ, Musani SK, Kerr KF, Schnabel RB, Lubitz SA, Sotoodehnia N, Redline S, Pfeufer A, Müller M, Evans DS, Nalls MA, Liu Y, Newman AB, Zonderman AB, Evans MK, Deo R, Ellinor PT, Paltoo DN, Newton-Cheh C, Benjamin EJ, Mehra R, Alonso A, Heckbert SR, Fox ER, Candidate-gene Association Resource (CARe) Consorti - PLoS Genet. (2011)

Bottom Line: This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8-3.0, p = 3 x 10⁻¹⁶) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%).African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts.Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Faculty of Medicine, Lund University, Lund, Sweden. gustav.smith@med.lu.se

ABSTRACT
The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5 x 10⁻⁸) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1-6.1, p = 3 x 10⁻²³). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8-3.0, p = 3 x 10⁻¹⁶) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

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Related in: MedlinePlus

PR interval association results for 2.8 million SNPs across 22 autosomes.Each dot represents one SNP. Plotted on the x-axis is physical position by chromosome and on the y-axis –log10(p-value).
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pgen-1001304-g002: PR interval association results for 2.8 million SNPs across 22 autosomes.Each dot represents one SNP. Plotted on the x-axis is physical position by chromosome and on the y-axis –log10(p-value).

Mentions: Genomic inflation was minimal in ARIC (λGC = 1.02) and MESA (λGC = 1.01) and modest in the family-based CFS (λGC = 1.10) and JHS (λGC = 1.08) studies, likely due to relatedness of some participants. Quantile-quantile plots of p-values were consistent with distributions at all but the lowest p-values (Figure S1). Genomic control was applied to test statistics in all cohorts. Genomic inflation in the meta-analysis was modest (λGC = 1.04); genomic control was applied again (Figure 1). The distribution of association results across the genome is shown in Figure 2. Twenty-four single nucleotide polymorphisms (SNPs) at four genomic loci reached genome-wide significance as shown in Table S1. We clustered these SNPs by pairwise correlation in the HapMap phase II YRI panel and observed five weakly correlated linkage disequilibrium bins (all pairwise r2 were <0.3). Results for the SNP with the lowest p-value in each cluster are shown in Table 2 and the correlation of these SNPs to SNPs reported in previous GWA studies of European and Asian ancestry are shown in Table 3.


Genome-wide association studies of the PR interval in African Americans.

Smith JG, Magnani JW, Palmer C, Meng YA, Soliman EZ, Musani SK, Kerr KF, Schnabel RB, Lubitz SA, Sotoodehnia N, Redline S, Pfeufer A, Müller M, Evans DS, Nalls MA, Liu Y, Newman AB, Zonderman AB, Evans MK, Deo R, Ellinor PT, Paltoo DN, Newton-Cheh C, Benjamin EJ, Mehra R, Alonso A, Heckbert SR, Fox ER, Candidate-gene Association Resource (CARe) Consorti - PLoS Genet. (2011)

PR interval association results for 2.8 million SNPs across 22 autosomes.Each dot represents one SNP. Plotted on the x-axis is physical position by chromosome and on the y-axis –log10(p-value).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037415&req=5

pgen-1001304-g002: PR interval association results for 2.8 million SNPs across 22 autosomes.Each dot represents one SNP. Plotted on the x-axis is physical position by chromosome and on the y-axis –log10(p-value).
Mentions: Genomic inflation was minimal in ARIC (λGC = 1.02) and MESA (λGC = 1.01) and modest in the family-based CFS (λGC = 1.10) and JHS (λGC = 1.08) studies, likely due to relatedness of some participants. Quantile-quantile plots of p-values were consistent with distributions at all but the lowest p-values (Figure S1). Genomic control was applied to test statistics in all cohorts. Genomic inflation in the meta-analysis was modest (λGC = 1.04); genomic control was applied again (Figure 1). The distribution of association results across the genome is shown in Figure 2. Twenty-four single nucleotide polymorphisms (SNPs) at four genomic loci reached genome-wide significance as shown in Table S1. We clustered these SNPs by pairwise correlation in the HapMap phase II YRI panel and observed five weakly correlated linkage disequilibrium bins (all pairwise r2 were <0.3). Results for the SNP with the lowest p-value in each cluster are shown in Table 2 and the correlation of these SNPs to SNPs reported in previous GWA studies of European and Asian ancestry are shown in Table 3.

Bottom Line: This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8-3.0, p = 3 x 10⁻¹⁶) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%).African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts.Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Faculty of Medicine, Lund University, Lund, Sweden. gustav.smith@med.lu.se

ABSTRACT
The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5 x 10⁻⁸) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1-6.1, p = 3 x 10⁻²³). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8-3.0, p = 3 x 10⁻¹⁶) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

Show MeSH
Related in: MedlinePlus