title: Genome-wide association studies of the PR interval in African Americans.
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.
authors.affiliation: Department of Cardiology, Faculty of Medicine, Lund University, Lund, Sweden. gustav.smith@med.lu.se
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.forename: Jared W
authors.initials: JW
authors.lastname: Magnani
authors.forename: Cameron
authors.initials: C
authors.lastname: Palmer
authors.forename: Yan A
authors.initials: YA
authors.lastname: Meng
authors.forename: Elsayed Z
authors.initials: EZ
authors.lastname: Soliman
authors.forename: Solomon K
authors.initials: SK
authors.lastname: Musani
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Kerr
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lubitz
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.forename: Susan
authors.initials: S
authors.lastname: Redline
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.forename: Alan B
authors.initials: AB
authors.lastname: Zonderman
authors.forename: Michele K
authors.initials: MK
authors.lastname: Evans
authors.forename: Rajat
authors.initials: R
authors.lastname: Deo
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Dina N
authors.initials: DN
authors.lastname: Paltoo
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.forename: Reena
authors.initials: R
authors.lastname: Mehra
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alonso
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.forename: Ervin R
authors.initials: ER
authors.lastname: Fox
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001283:Atrioventricular Node / Q000503:physiopathology; D004562:Electrocardiography; D005260:Female; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000235:genetics; D044465:White People
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D009124:Muscle Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009363:Neoplasm Proteins; C568317:SCN10A protein, human; C568320:SCN5A protein, human; D015222:Sodium Channels; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5