Genome-Wide Association Studies of the PR Interval in African Americans

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.

[1]  Scott M. Williams,et al.  Genetic analysis of African populations: human evolution and complex disease , 2002, Nature Reviews Genetics.

[2]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[3]  Joshua M. Korn,et al.  Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs , 2008, Nature Genetics.

[4]  Kari Stefansson,et al.  Several common variants modulate heart rate, PR interval and QRS duration , 2010, Nature Genetics.

[5]  Mark I. McCarthy,et al.  Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies , 2008, PloS one.

[6]  Daniel W. Jones,et al.  Toward resolution of cardiovascular health disparities in African Americans: design and methods of the Jackson Heart Study. , 2005, Ethnicity & disease.

[7]  Marcia M. Nizzari,et al.  Candidate Gene Association Resource (CARe): Design, Methods, and Proof of Concept , 2010, Circulation. Cardiovascular genetics.

[8]  Mark N. Wass,et al.  Genetic variation in SCN10A influences cardiac conduction , 2010, Nature Genetics.

[9]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[10]  F. Cappuccio,et al.  Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia , 2002, Science.

[11]  Zhu-ming Zhang,et al.  Ethnic Distribution of ECG Predictors of Atrial Fibrillation and Its Impact on Understanding the Ethnic Distribution of Ischemic Stroke in the Atherosclerosis Risk in Communities (ARIC) Study , 2009, Stroke.

[12]  Joshua M. Korn,et al.  Integrated detection and population-genetic analysis of SNPs and copy number variation , 2008, Nature Genetics.

[13]  D. Reich,et al.  Sensitive Detection of Chromosomal Segments of Distinct Ancestry in Admixed Populations , 2009, PLoS genetics.

[14]  R. Havlik,et al.  Variability of heart rate, P-R, QRS and Q-T durations in twins. , 1980, Journal of Electrocardiology.

[15]  A. Folsom,et al.  The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. , 1989, American journal of epidemiology.

[16]  M. Daly,et al.  Estimation of the multiple testing burden for genomewide association studies of nearly all common variants , 2008, Genetic epidemiology.

[17]  Christian Gieger,et al.  Genome-wide association study of PR interval , 2010, Nature Genetics.

[18]  M. Daly,et al.  Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae. , 2009, Heart rhythm.

[19]  David Reich,et al.  A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia , 2009, Nature Genetics.

[20]  Scott M. Williams,et al.  The Genetic Structure and History of Africans and African Americans , 2009, Science.

[21]  L Sun,et al.  Statistical tests for detection of misspecified relationships by use of genome-screen data. , 2000, American journal of human genetics.

[22]  D. Lykken,et al.  Genetic factors in the electrocardiogram and heart rate of twins reared apart and together. , 1989, The American journal of cardiology.

[23]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[24]  M. Daly,et al.  Methods for high-density admixture mapping of disease genes. , 2004, American journal of human genetics.

[25]  G. Abecasis,et al.  Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians , 2006, PLoS genetics.

[26]  D. Levy,et al.  Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study , 2007, BMC Medical Genetics.

[27]  D. Vlahov,et al.  MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis , 2008, Nature Genetics.

[28]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[29]  S. Redline,et al.  The familial aggregation of obstructive sleep apnea. , 1995, American journal of respiratory and critical care medicine.

[30]  Ming-Huei Chen,et al.  GWAF: an R package for genome-wide association analyses with family data , 2010, Bioinform..

[31]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[32]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[33]  R. Kronmal,et al.  Multi-Ethnic Study of Atherosclerosis: objectives and design. , 2002, American journal of epidemiology.

[34]  M. Gold,et al.  Long-term Outcomes in Individuals With Prolonged PR Interval or First-Degree Atrioventricular Block , 2010 .

[35]  Zachary A. Szpiech,et al.  Genome-wide association studies in diverse populations , 2010, Nature Reviews Genetics.