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

Smith, JG and Magnani, JW and Palmer, C and Meng, YA and Soliman, EZ and Musani, SK and Kerr, KF and Schnabel, RB and Lubitz, SA and Sotoodehnia, N and Redline, S and Pfeufer, A and Müller, M and Evans, DS and Nalls, MA and Liu, Y and Newman, AB and Zonderman, AB and Evans, MK and Deo, R and Ellinor, PT and Paltoo, DN and Newton-Cheh, C and Benjamin, EJ and Mehra, R and Alonso, A and Heckbert, SR and Fox, ER (2011) Genome-wide association studies of the PR interval in African Americans. PLoS Genetics, 7 (2). ISSN 1553-7390

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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.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID 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 ANEWMAN@pitt.edu ANEWMAN Zonderman, AB Evans, MK Deo, R Ellinor, PT Paltoo, DN Newton-Cheh, C Benjamin, EJ Mehra, R Alonso, A Heckbert, SR Fox, ER
Date:	1 February 2011
Date Type:	Publication
Journal or Publication Title:	PLoS Genetics
Volume:	7
Number:	2
DOI or Unique Handle:	10.1371/journal.pgen.1001304
Schools and Programs:	School of Public Health > Epidemiology
Refereed:	Yes
ISSN:	1553-7390
MeSH Headings:	Adult; African Americans--genetics; Aged; Arrhythmias, Cardiac--genetics; Asian Continental Ancestry Group--genetics; Atrioventricular Node--physiopathology; Electrocardiography; European Continental Ancestry Group; Female; Genome-Wide Association Study; Homeodomain Proteins--genetics; Humans; Male; Middle Aged; Muscle Proteins--genetics; Neoplasm Proteins--genetics; Polymorphism, Single Nucleotide--genetics; Sodium Channels--genetics; T-Box Domain Proteins--genetics
Other ID:	NLM PMC3037415
PubMed Central ID:	PMC3037415
PubMed ID:	21347284
Date Deposited:	07 Aug 2012 15:46
Last Modified:	25 Jun 2021 21:55
URI:	http://d-scholarship.pitt.edu/id/eprint/13352

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