Date Published: June 28, 2019
Publisher: Public Library of Science
Author(s): Brenton R. Swenson, Tin Louie, Henry J. Lin, Raúl Méndez-Giráldez, Jennifer E. Below, Cathy C. Laurie, Kathleen F. Kerr, Heather Highland, Timothy A. Thornton, Kelli K. Ryckman, Charles Kooperberg, Elsayed Z. Soliman, Amanda A. Seyerle, Xiuqing Guo, Kent D. Taylor, Jie Yao, Susan R. Heckbert, Dawood Darbar, Lauren E. Petty, Barbara McKnight, Susan Cheng, Natalie A. Bello, Eric A. Whitsel, Craig L. Hanis, Mike A. Nalls, Daniel S. Evans, Jerome I. Rotter, Tamar Sofer, Christy L. Avery, Nona Sotoodehnia, Amanda Ewart Toland.
The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.
We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.
We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos. Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.
The duration of the QRS complex on a resting, standard 12-lead electrocardiogram (ECG) represents the electrical depolarization of the ventricles as an impulse travels through the cardiac conduction system and the ventricular myocardium. Delay in cardiac ventricular conduction results in increased QRS durations, and has been shown to predict heart failure prognosis,[1, 2] sudden death, and cardiovascular (CV) mortality in patients with and without left ventricular dysfunction, independent of traditional CV risk factors. In turn, shortening of the QRS duration with the use of cardiac-resynchronization therapy (CRT) has been shown to decrease heart-failure related events in patients with QRS prolongation.
Our GWAS included 15,124 Hispanic/Latino individuals from four contributing cohorts. Baseline characteristics varied substantially across the four cohorts. For example, WHI is a study of women only. The average age of the participants across the four cohorts ranged from 45 to 61 years. The prevalence of hypertension and diabetes across the four cohorts ranged from 26% to 42% for hypertension and 8% to 46% for diabetes (S1 Table).
Our GWAS meta-analysis of four cohorts (15,124 individuals) of Hispanic/Latino ethnicity found 9 index SNPs across 6 loci with genome-wide significant associations with QRS duration. Two loci were novel (MYOCD and SYT1), and four loci (SCN5A-SCN10A, CDKN1A, HAND1, and VTI1A) were previously identified in QRS GWAS analyses of European and African-descent individuals. This is the first GWAS of QRS duration in Hispanics/Latinos, a genetically admixed group, comprised of European, African, and Native American ancestry populations, coming from what is now Mexico, Central America, South America, and the Caribbean islands. Hispanics/Latinos were excluded in prior published QRS duration GWAS, and the genetic as well as non-genetic determinants of cardiovascular risk remain under-examined in this population.[25, 26]