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The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10 -8 ) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10 -8 ) and multi-trait analysis (P = 2.9 × 10 -9 ) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

Background: Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized., Objective: The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767)., Methods: We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10 -8 ) or suggestive (P <10 -6 ) significance thresholds., Results: Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms., Conclusion: This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74g <-0.55) and blood pressure (-0.35g <-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

Aims: The aim of this study was to examine the bidirectional association between atrial fibrillation and congestive heart failure (CHF) in older adults., Methods: We studied the association of atrial fibrillation at entry with incident CHF (N = 5281; 85% white, 42% male) and the association of CHF at entry with incident atrial fibrillation (N = 5233; 85% white, 42% male) in the Cardiovascular Health Study (CHS). Baseline atrial fibrillation was identified during the study electrocardiogram and by self-reported history, and incident cases were identified during subsequent study electrocardiograms and hospitalization data. Baseline CHF was identified by self-reported history and adjudication of medical records, and incident cases were identified using hospitalization data. Cox regression was used to compute hazard ratios and 95% confidence intervals (CIs) for the association between atrial fibrillation and incident CHF, and CHF and incident atrial fibrillation, separately., Results: Over a median follow-up of 12.6 years, 534 (10%) participants developed atrial fibrillation. CHF was associated with an increased risk of atrial fibrillation (hazard ratio 2.0, 95% CI 1.4, 3.0). A total of 1692 (32%) participants developed CHF over a median follow-up of 11.7 years and atrial fibrillation was associated with an increased risk of CHF (hazard ratio 1.9, 95% CI 1.5, 2.2)., Conclusion: Our results suggest that a bidirectional relationship exists between atrial fibrillation and CHF, with each condition influencing the development of the other.

The relationships between ambient PM(2.5) and PM(10) and arrhythmia and the effect modification by cigarette smoking were investigated. Data from U.S. Environmental Protection Agency (EPA) air quality monitors and an established national-scale, log-normal kriging method were used to spatially estimate daily mean concentrations of PM at addresses of 57,422 individuals from 59 examination sites in 24 U.S. states in 1999-2004. The acute and subacute exposures were estimated as mean, geocoded address-specific PM concentrations on the day of, 0-2 d before, and averaged over 30 d before the electrocardiogram (ECG) (Lag(0); Lag(1); Lag(2); Lag(1-30)). At the time of standard 12-lead resting ECG, the mean age (SD) of participants was 67.5 (6.9) yr (84% non-Hispanic White; 6% current smoker; 15% with coronary heart disease; 5% with ectopy). After the identification of significant effect modifiers, two-stage random-effects models were used to calculate center-pooled odds ratios and 95% confidence intervals (OR, 95% CI) of arrhythmia per 10 mug/m(3) increase in PM concentrations. Among current smokers, Lag(0) and Lag(1) PM concentrations were significantly associated ventricular ectopy (VE)-the OR (95% CI) for VE among current smokers was 2 (1.32-3.3) and 1.32 (1.07-1.65) at Lag(1) PM(2.5) and PM(10), respectively. The interactions between current smoking and acute exposures (Lag(0); Lag(1); Lag(2)) were significant in relationship to VE. Acute exposures were not significantly associated with supraventricular ectopy (SVE), or with VE among nonsmokers. Subacute (Lag(1-30)) exposures were not significantly associated with arrhythmia. Acute PM(2.5) and PM(10) exposure is directly associated with the odds of VE among smokers, suggesting that they are more vulnerable to the arrhythmogenic effects of PM.