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Title: Genome-Wide Association Studies of the PR Interval in African Americans}
Article:
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. 5×10−8) 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 = 3×10−23). This SNP was also associated with PR interval( beta = 2. 4 msec per minor allele, 95% CI = 1. 8–3. 0, p = 3×10−16) 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.
Introduction:
The electrocardiogram is an important clinical tool that provides a graphical representation of the electrical activity of the heart as captured by skin surface electrodes. The electrocardiographic PR interval represents conduction through the atria and AV node, and impaired conduction through these tissues is a central pathogenic mechanism in many cardiac arrhythmias. Prolongation of the PR interval is a risk factor for long-term atrial fibrillation, heart block, and all-cause mortality[1]. A substantial proportion of the variability of the PR interval is explained by genetic factors with heritability estimates ranging between 30 and 50% in populations of European and Asian ancestry[2]–[7]. Identification of the specific alleles underlying the heritability of the PR interval might provide novel insights into molecular electrophysiology, lead to novel drug targets for arrhythmia treatment, and facilitate genetic prediction of arrhythmia risk and response to antiarrhythmics. Genome-wide association( GWA) studies have identified nine loci associated with PR interval duration in populations of European[6],[8] or South Asian ancestry[9]. Four of these associations have been replicated[6],[9]. However, there is a general paucity of GWA studies performed in populations of African ancestry[10] and none have been performed for PR interval duration which has been suggested to be longer in individuals of African than European ancestry[11]. Samples of African ancestry typically have shorter-range linkage disequilibrium( LD) than samples of European or Asian ancestry, potentially reducing genomic coverage in GWA studies using fixed arrays. However, samples of African ancestry offer greater genetic diversity; European and Asian populations have experienced a loss of allelic diversity since the out-of-Africa founding events[12],[13]. Thus, unique alleles influencing complex traits may be present in samples of African ancestry and shorter-range LD can facilitate narrowing of association signals. We studied the association of genetic ancestry with PR interval and performed a GWA study in 6, 247 African Americans from four cohorts as part of the Candidate-gene Association Resource( CARe) consortium including the Atherosclerosis Risk in Communities( ARIC) study, the Cleveland Family Study( CFS), the Jackson Heart Study( JHS) and the Multi-Ethnic Study of Atherosclerosis( MESA). Replication of genome-wide significant associations was attempted by direct genotyping in 2, 022 African Americans from the Health, Aging, and Body Composition Study( Health ABC) and the Healthy Aging in Neighborhoods of Diversity across the Life Span Study( HANDLS).
Discussion:
We performed a meta-analysis of GWA studies of the PR interval duration in individuals of African ancestry from four cohorts. We used a stringent significance threshold of 2. 5×10−8, as previous genetic analyses have suggested twice as many independent SNPs in samples of African ancestry compared to European ancestry[14]. In two cohorts and in the meta-analysis we observed a genome-wide significant association with the SNP rs3922844 in SCN5A that explains approximately 2% of variability in PR interval duration. The SNP was not correlated with rs11708996, another SNP in SCN5A associated with PR interval duration in prior GWA studies of subjects of European ancestry[8], and had a larger effect estimate than rs11708996. We, therefore, examined the result for rs3922844 in a previously reported GWA study of PR interval in subjects of European ancestry[8] and observed genome-wide significant association but with a smaller effect estimate as compared to our study( 5. 1 msec, 95% CI = 4. 1–6. 1 versus 2. 4 msec, 95% CI = 1. 8–3. 0, p for heterogeneity <0. 001). Thus, we have evaluated genetic variants associated with PR interval duration in subjects of African American ancestry and identified an association signal from SCN5A with a larger effect size in individuals of African American compared to European ancestry. We consider direct prolongation of the PR interval by rs3922844 unlikely given the differing effect sizes in individuals of African American and European ancestry. No SNP catalogue, including HapMap, used as reference panel for imputation in our study, includes all common sequence variants. We consider it more likely that rs3922844 is correlated with one or several causal variants and that the varying effect sizes result from differences in LD patterns across populations. For example, two variants with opposing effects could exist at the locus, with overlapping signals in Europeans but with isolation of individual signals in African Americans due to breakdown of linkage disequilibrium. The SNP rs3922844 was not directly genotyped in our samples but was imputed with high imputation quality as measured by the average ratio of observed variance to that expected by the Hardy-Weinberg equilibrium. We note that no SNPs included on our genotyping platform had an r2>0. 2 with rs3922844 in the African( YRI) HapMap panel. A small cluster of genotyped SNPs were well correlated with rs3922844 in the European( CEU) HapMap panel( r2 = 0. 6–0. 8) as shown in Figure 3 but none of these reached a p-value less than 10−4. These observations suggest that the association was detected due to correlation of rs3922844 with multiple, weakly correlated, genotyped SNPs. Alternatively, a strong gene-environment interaction for rs3922844 could result in large differences in effect estimates across populations subject to differential environmental exposures or other genetic effects. Large-scale resequencing or imputation from large-scale resequencing efforts such as the 1000 Genomes Project, and functional experiments will ultimately be necessary to identify the causal variants. Although allelic heterogeneity between families is well established for monogenic diseases, little is known about common variants across different populations. Recently identified findings include different association signals at the locus containing KCNQ1 with type 2 diabetes in European and Asian cohorts[10], at MYH9 with focal segmental glomerulosclerosis[15] and a MYBPC3 variant that causes cardiomyopathy and is only polymorphic in Asian populations[16]. Allelic heterogeneity is conceptually important and highlights the value of genetic association studies spanning diverse racial and ethnic populations. Studies across multiple populations may identify novel disease loci and genetic factors underlying differences in risk by race. Our results do not provide support for allelic heterogeneity across populations for PR interval, although limited power may have failed to detect such effects. Genetic admixture studies have estimated that, on average, modern African American genomes have approximately 80–90% African and 10–20% European ancestry[17], which is well in line with our global ancestry analyses. It is important to note that there is great genetic diversity across the African continent. Our study included African Americans, who predominantly have an ancestral origin in Central and West Africa. It is possible that GWA studies in other samples of African ancestry might identify additional association signals. The clinical impact of our findings merit further exploration. For example, a missense variant in SCN5A, S1103Y( rs7626962), which is polymorphic in African Americans but very rare in Europeans, has been associated with a markedly increased risk of ventricular arrhythmias[18]. This variant was not correlated with rs3922844 in the YRI panel of HapMap phase III( r2 = 0. 04). Furthermore, African Americans have been shown to have a lower incidence of atrial fibrillation than Europeans. Longer PR interval duration( difference in means 11. 8 msec) has also been reported in African Americans compared to Europeans in the ARIC study[11]. We were able to confirm this observation in ARIC using genetic ancestry, with a similar magnitude( 13. 3 msec longer with complete African compared to complete European ancestry, p = 0. 009). However, we did not observe differences by genetic ancestry in CFS, JHS or MESA. This discrepancy could be due to differences in trans-African ancestry or other factors. Our results further indicate that common variants are unlikely to explain a large part of any ancestry-related variation in atrial and atrioventricular nodal conduction. The strongest variant observed here explained 2% of PR interval variability. It seems more likely that any ancestry-related differences in atrial conduction are due to rare variants, but this awaits further testing. Additional studies in populations with atrial fibrillation or sudden cardiac death will be necessary to determine the impact of the SNPs identified in our study on clinical outcomes. In our meta-analysis, we also observed genome-wide significant association signals of SNPs in SCN10A, TBX5 and MEIS1, which are correlated with SNPs reported in previous GWA studies in individuals of European ancestry. The lowest p-value in the SCN10A cluster of SNPs was not observed in the previously described missense variant( rs6795970)[6],[9] but in an intronic SNP( rs6798015). The effect estimate was highest for the missense SNP but it also had the lowest minor allele frequency in the cluster, a lower allele frequency than in European( CEU) and Asian( JPT and CHB) HapMap panels. No evidence that the missense variant explains the association with PR interval has been published yet. Although it is possible that another SNP mediates the association, we find it more likely that the weaker p-value for the intronic SNP in our meta-analysis reflects differences in imputation quality or chance difference in the strength of the observed association. To ultimately identify the causal variants in each population, large-scale resequencing and functional experiments will be necessary. Four genome-wide association studies for PR interval duration have been published previously. The first study identified an association with SNPs in SCN5A in a Micronesian founder population, but no SNP reached genome-wide significance[5]. A large study in individuals of European ancestry identified nine loci of genome-wide significance[8], including ARHGAP24, CAV1/CAV2, MEIS1, NKX2-5, SCN5A, SCN10A, SOX5, TBX5/TBX3 and WNT11. A third study in Icelanders identified and replicated significant associations with four of these loci[6]; ARHGAP24, CAV1, SCN10A and TBX5/TBX3. Finally, a study in individuals of Asian ancestry identified and replicated association with SNPs in SCN10A[9]. Here, we have reported genome-wide significant associations in African Americans with SNPs in strong LD with the previously reported SNPs at four of these loci; MEIS1, SCN5A, SCN10A and TBX5/TBX3. These findings demonstrate the relevance of these common alleles to individuals of African ancestry. Our study has a number of limitations. All GWA studies suffer risk of false positive associations due to multiple testing, which is higher in samples of African ancestry where two million independent SNPs have been described[14]. We therefore applied a stringent significance threshold( 2. 5×10−8) to account for the approximately two million common variant tests estimated to exist across the genome. Large sample sizes are required to achieve such stringent significance levels. Our significant findings are thus unlikely to be false positives, especially as association signals at the same loci have been observed in European studies. However, even in the meta-analysis our study was underpowered to detect both common variants of small effect and rare variants. Measurement error in PR duration and heterogeneity between cohorts may further contribute to loss of power. Another potential problem encountered in genetic association studies is population stratification or confounding by ancestry. We sought to address this issue by filtering out individuals with cryptic relatedness or unlikely to be of African ancestry, adjusting for principal components of genome-wide data that describe within-population genetic variation, using family-based methods where appropriate and applying genomic control. In conclusion, our results suggest that genetic loci underlying complex traits may be in large part the same across ancestral populations. However, association signals may show different effects across ethnic and racial populations and multiple association signals may exist at these loci. We anticipate that large-scale resequencing and functional experiments will ultimately identify the causal variants specific to each population.
We performed genome-wide association studies in African American participants from four population-based cohorts to identify genetic variation that correlates with variation in PR interval duration , an electrocardiographic measure of conduction through the atria and atrioventricular node . We observed a strong signal within the gene encoding the cardiac sodium channel , SCN5A , with genome-wide significant association ( p<2 . 5×10−8 ) in two cohorts and in a meta-analysis of four cohorts with African Americans . We replicated this association in two additional cohorts of African Americans and in Europeans ( p = 3×10−16 ) . The signal explains 2% of PR duration variability in African Americans and 0 . 5% in Europeans . In further meta-analysis , we observed genome-wide significant associations for single nucleotide polymorphisms in SCN10A , MEIS1 , TBX5 , corresponding to signals observed in people of European and Asian descent . We found an association of genetic ancestry and PR interval in one but not the other three cohorts . Our findings provide the first demonstration of the relevance of these loci to individuals of African ancestry and identify an association signal from SCN5A that is more strongly associated with PR interval in African Americans .