Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, USA.
Nature Genetics (Impact Factor: 29.35). 11/2010; 42(12):1068-76. DOI: 10.1038/ng.716
Source: PubMed


The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

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    • "It is well established that many cardiac traits and susceptibility to heart disease are heritable [1], [2], [3], [4], [5], [6], [7]. Several genome-wide association studies (GWAS) have uncovered common genetic variation, in the form of single nucleotide polymorphisms (SNPs), impacting on cardiac traits such as susceptibility to atrial fibrillation [8], ventricular fibrillation [9], heart rate [10] and electrocardiographic (ECG) indices of cardiac conduction [11], [12], [13], [14] and repolarization [15], [16]. There is widespread consensus that functional studies of GWAS-defined loci will advance our understanding of the molecular underpinnings of the associated traits. "
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    ABSTRACT: In recent years genome-wide association studies (GWAS) have uncovered numerous chromosomal loci associated with various electrocardiographic traits and cardiac arrhythmia predisposition. A considerable fraction of these loci lie within inter-genic regions. The underlying trait-associated variants likely reside in regulatory regions and exert their effect by modulating gene expression. Hence, the key to unraveling the molecular mechanisms underlying these cardiac traits is to interrogate variants for association with differential transcript abundance by expression quantitative trait locus (eQTL) analysis. In this study we conducted an eQTL analysis of human heart. For a total of 129 left ventricular samples that were collected from non-diseased human donor hearts, genome-wide transcript abundance and genotyping was determined using microarrays. Each of the 18,402 transcripts and 897,683 SNP genotypes that remained after pre-processing and stringent quality control were tested for eQTL effects. We identified 771 eQTLs, regulating 429 unique transcripts. Overlaying these eQTLs with cardiac GWAS loci identified novel candidates for studies aimed at elucidating the functional and transcriptional impact of these loci. Thus, this work provides for the first time a comprehensive eQTL map of human heart: a powerful and unique resource that enables systems genetics approaches for the study of cardiac traits.
    PLoS ONE 05/2014; 9(5):e97380. DOI:10.1371/journal.pone.0097380 · 3.23 Impact Factor
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    • "This finding was highly interesting since SCN10A had never been linked to cardiac conduction before. Functional follow-up studies revealed that SCN10A is expressed in cardiomyocytes of the human ventricular conduction system and that loss of SCN10A has an apparent effect on both PR interval and QRS duration in mice (Chambers et al., 2010; Sotoodehnia et al., 2010). However, its role in cardiac conduction disease remains to be established (Verkerk et al., 2012; Yang et al., 2012). "
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    ABSTRACT: The electrical activity of the heart depends on the correct interplay between key transcription factors and cis-regulatory elements, which together regulate the proper heterogeneous expression of genes encoding for ion channels and other proteins. Genome-wide association studies of ECG parameters implicated genetic variants in the genes for these factors and ion channels modulating conduction and depolarization. Here, we review recent insights into the regulation of localized expression of ion channel genes and the mechanism by which a single-nucleotide polymorphism (SNP) associated with alterations in cardiac conduction patterns in humans affects the transcriptional regulation of the sodium channel genes, SCN5A and SCN10A. The identification of regulatory elements of electrical activity genes helps to explain the impact of genetic variants in non-coding regulatory DNA sequences on regulation of cardiac conduction and the predisposition for cardiac arrhythmias.
    Trends in cardiovascular medicine 12/2013; 24(3). DOI:10.1016/j.tcm.2013.09.001 · 2.91 Impact Factor
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    • "Further investigation of Cip/Kip knockout mice with an eye towards cardiac defects is therefore warranted. Furthermore, recent genome wide association studies have linked CDKN1A (p21) with QRS duration in European cohorts (Holm et al., 2010; Sotoodehnia et al., 2010). These studies are the first to link cell cycling genes with VCS function in the general population, and places new focus on pocket protein-dependent pathways as critical regulators of the specialized conduction system. "
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    ABSTRACT: During development, the ventricular conduction system (VCS) arises from the trabecular or spongy myocardium. VCS and trabecular myocytes proliferate at a significantly slower rate than compact zone myocardial cells, establishing a transmural cell cycle gradient. The molecular determinants of VCS/trabecular myocyte cell cycle arrest are not known. Given the importance of pocket proteins (Rb, p107 and p130) in mediating G0/G1 arrest in many cell types, we examined the role of this gene family in regulating cell cycle exit of the trabecular myocardium and ventricular conduction system. Using a combinatorial knockout strategy, we found that graded loss of pocket proteins results in a spectrum of heart and lung defects. p107/p130 double knockout (dKO) hearts manifest dysregulated proliferation within the compact myocardium and trabecular bases, while the remaining trabecular region cell cycle exits normally. Consequently, dKO hearts exhibit defective cardiac compaction, septal hyperplasia and biventricular outflow tract obstruction, while the VCS appears relatively normal. Loss of all three pocket proteins (3KO) is necessary to completely disrupt the transmural cell cycle gradient. 3KO hearts exhibit massive overgrowth of the trabecular myocardium and ventricular conduction system, which leads to fetal heart failure and death. Hearts carrying a single pocket protein allele are able to maintain the transmural cell cycle gradient. These results demonstrate the exquisite sensitivity of trabecular and conduction myocytes to pocket protein function during ventricular chamber development.
    Biology Open 09/2013; 2(9):968-78. DOI:10.1242/bio.20135785 · 2.42 Impact Factor
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