Genome-wide association studies of cardiac electrical phenotypes

Glinge, Charlotte; Lahrouchi, Najim; Jabbari, Reza; Tfelt-Hansen, Jacob; Bezzina, Connie R.

doi:10.1093/cvr/cvaa144

Cited by 20 publications

(14 citation statements)

References 104 publications

(123 reference statements)

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“…Fifth, this study did not encompass ventricular tachycardia or ventricular fibrillation, as large-scale population-based GWAS summary statistics on ventricular arrhythmias are currently unavailable. Recruiting patients with ventricular fibrillation in the setting of acute myocardial infarction is challenging when compared to the ease of recruitment of atrial fibrillation patients ( 50 ). Existing GWAS primarily focus on electrophysiological parameters that highly correlated with ventricular tachyarrhythmia, such as PR interval ( 51 ), QT interval ( 50 , 52 ), or specific diseases like Brugada syndrome ( 53 ) or long QT syndrome ( 54 ), which are predominantly characterized by ventricular arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

“…Recruiting patients with ventricular fibrillation in the setting of acute myocardial infarction is challenging when compared to the ease of recruitment of atrial fibrillation patients ( 50 ). Existing GWAS primarily focus on electrophysiological parameters that highly correlated with ventricular tachyarrhythmia, such as PR interval ( 51 ), QT interval ( 50 , 52 ), or specific diseases like Brugada syndrome ( 53 ) or long QT syndrome ( 54 ), which are predominantly characterized by ventricular arrhythmias. Sixth, the “all types of arrhythmias” analyzed in the study represent a collection of phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology

et al. 2023

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BackgroundCardiac arrhythmia is a common disease associated with high mortality and morbidity. Circulating leukocyte counts, which serve as a biomarker for assessing systemic immune status, have been linked to arrhythmias in observational studies. However, observational studies are plagued by confounding factors and reverse causality, whether alterations in circulating leukocyte components are causally associated with arrhythmias remains uncertain. The present study explored this question based on genetic evidence.Methods and findingsWe performed Mendelian randomization (MR) analysis to evaluate whether alterations in leukocyte counts affect aggregated risk of all types of arrhythmia or risk of five specific types of arrhythmia. Single-nucleotide polymorphisms serving as proxies for leukocyte differential counts were retrieved from the Blood Cell Consortium, and statistical data on arrhythmias were obtained from the UK Biobank), FinnGenand a meta-analysis of genome-wide association studies for atrial fibrillation. We applied inverse variance-weighted method as the primary analysis, complemented by a series of sensitivity analyses. Bidirectional analyses were conducted to assess reverse causality. Finally, multivariable MR was performed to study the joint effects of multiple risk factors. We found that genetically predicted differential leukocyte counts were not significantly associated with aggregated occurrence of all types of arrhythmia. In contrast, each 1-standard deviation increase in lymphocyte count was associated with 46% higher risk of atrioventricular block (OR 1.46, 95% CI 1.11–1.93, p=0.0065). A similar effect size was observed across all MR sensitivity analyses, with no evidence of horizontal pleiotropy. Reverse MR analysis suggested that atrioventricular block was unlikely to cause changes in lymphocyte count. Primary MR analysis based on the inverse-variance weighted method suggested that changes in neutrophil count alter risk of right bundle branch block, and changes in basophil count alter risk of atrial fibrillation. However, these causal relationships were not robust in sensitivity analyses. We found no compelling evidence that neutrophil or lymphocyte counts cause atrial fibrillation.ConclusionOur data support higher lymphocyte count as a causal risk factor for atrioventricular block. These results highlight the importance of immune cells in the pathogenesis of specific cardiac conduction disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology

et al. 2023

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“…Several genomic loci have been associated with these traits by GWAS in the general population, providing clues into the biological pathways underlying the regulation of cardiac electrical function. Although as many as 255 independent SNPs were associated with at least one ECG parameter, they still explain a small proportion of the heritabilities of these phenotypes in the population (Glinge et al., 2020), demonstrating that GWAS still have considerable potential to unravel novel mechanisms modulating the cardiovascular system.…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide association studies: utility and limitations for research in physiology

Pereira Ciochetti,

Lugli‐Moraes,

Santos da Silva

et al. 2023

The Journal of Physiology

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Physiological systems are subject to interindividual variation encoded by genetics. Genome‐wide association studies (GWAS) operate by surveying thousands of genetic variants from a substantial number of individuals and assessing their association to a trait of interest, be it a physiological variable, a molecular phenotype (e.g. gene expression), or even a disease or condition. Through a myriad of methods, GWAS downstream analyses then explore the functional consequences of each variant and attempt to ascertain a causal relationship to the phenotype of interest, as well as to delve into its links to other traits. This type of investigation allows mechanistic insights into physiological functions, pathological disturbances and shared biological processes between traits (i.e. pleiotropy). An exciting example is the discovery of a new thyroid hormone transporter (SLC17A4) and hormone metabolising enzyme (AADAT) from a GWAS on free thyroxine levels. Therefore, GWAS have substantially contributed with insights into physiology and have been shown to be useful in unveiling the genetic control underlying complex traits and pathological conditions; they will continue to do so with global collaborations and advances in genotyping technology. Finally, the increasing number of trans‐ancestry GWAS and initiatives to include ancestry diversity in genomics will boost the power for discoveries, making them also applicable to non‐European populations.

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“…This can compromise the analysis of data from high-throughput methodologies, such as genome-wide association studies (GWAS), exome sequencing, transcriptomics, and proteomics. High-throughput analyses are powerful tools that are increasingly being used to investigate cardiovascular diseases, many of which are associated with CCS dysfunction ( Glinge et al, 2020 ). Interpretation of these data relies on access to high-quality descriptions of cellular and physiological roles of genes and proteins.…”

Section: Introductionmentioning

confidence: 99%

GOing Forward With the Cardiac Conduction System Using Gene Ontology

Cook

Lovering

2022

Front. Genet.

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The cardiac conduction system (CCS) comprises critical components responsible for the initiation, propagation, and coordination of the action potential. Aberrant CCS development can cause conduction abnormalities, including sick sinus syndrome, accessory pathways, and atrioventricular and bundle branch blocks. Gene Ontology (GO; http://geneontology.org/) is an invaluable global bioinformatics resource which provides structured, computable knowledge describing the functions of gene products. Many gene products are known to be involved in CCS development; however, this information is not comprehensively captured by GO. To address the needs of the heart development research community, this study aimed to describe the specific roles of proteins reported in the literature to be involved with CCS development and/or function. 14 proteins were prioritized for GO annotation which led to the curation of 15 peer-reviewed primary experimental articles using carefully selected GO terms. 152 descriptive GO annotations, including those describing sinoatrial node and atrioventricular node development were created and submitted to the GO Consortium database. A functional enrichment analysis of 35 key CCS development proteins confirmed that this work has improved the in-silico interpretation of this CCS dataset. This work may improve future investigations of the CCS with application of high-throughput methods such as genome-wide association studies analysis, proteomics, and transcriptomics.

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Genome-wide association studies of cardiac electrical phenotypes

Cited by 20 publications

References 104 publications

Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology

Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology

Genome‐wide association studies: utility and limitations for research in physiology

GOing Forward With the Cardiac Conduction System Using Gene Ontology

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