Common variants at ten loci influence QT interval duration in the QTGEN Study

Newton‐Cheh, Christopher; Eijgelsheim, Mark; Rice, Kenneth; Bakker, Paul I. W. de; Yin, Xiaoyan; Estrada, Karol; Bis, Joshua C.; Marciante, Kristin D.; Rivadeneira, Fernando; Noseworthy, Peter A.; Sotoodehnia, Nona; Smith, Nicholas L.; Rotter, Jerome I.; Kors, Jan A.; Witteman, Jacqueline C. M.; Hofman, Albert; Heckbert, Susan R.; O’Donnell, Christopher J; Uitterlinden, André G.; Psaty, Bruce M.; Lumley, Thomas; Larson, Martin G.; Stricker, Bruno H. Ch.

doi:10.1038/ng.364

Cited by 392 publications

(391 citation statements)

References 43 publications

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“…34 The NOS1AP association was further substantiated by two later GWAS in a large sample set of nearly 30 000 samples for the initial and replication studies. 35,36 Besides confirming the previously known gene, several new loci were also identified. Interestingly, both studies also found KCNQ1 to be associated with the trait; this is because the gene was also associated with type-2 diabetes (T2D).…”

Section: Gwas After Hapmap-the Progress Over the Past 5 Years The Firsupporting

confidence: 68%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

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It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio o1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

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Section: Gwas After Hapmap-the Progress Over the Past 5 Years The Firsupporting

confidence: 68%

The pursuit of genome-wide association studies: where are we now?

et al. 2010

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“…The SNP rs846111 actually lies within the open reading frame of the RNF207 gene and not in its 3Ј untranslated region as reported (10,11). Interestingly, RNF207 contains a RING domain (17), suggesting that the protein may be a ubiquitin ligase.…”

mentioning

confidence: 82%

“…One SNP associated with prolongation of the QT interval (approximately 1.7 (10, 11) or 2.9 ms (16)) has been mapped within the gene encoding RNF207 (10,11). The SNP rs846111 actually lies within the open reading frame of the RNF207 gene and not in its 3Ј untranslated region as reported (10,11).…”

mentioning

confidence: 86%

“…No sequence homology is found in the C-terminal non-homologous region (CNHR). Also shown is the SNP (G603A) in human RNF207, which is associated with QT interval prolongation (10,11,16).…”

Section: Action Potential Prolongation and Conduction Velocity Slowinmentioning

confidence: 99%

“…Because approximately one-third of QT interval variability is heritable (6 -8), a number of genome-wide association studies have been performed to identify genes underlying this variation (9 -14). For example, two recent genome-wide association studies (10,11) identified five novel loci associated with the QT interval. These polymorphisms may cumulatively contribute to QT interval variation and, hence, to the net risk for cardiac arrhythmias (5).…”

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confidence: 99%

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RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation

Roder

Werdich

et al. 2014

Journal of Biological Chemistry

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Background: A genetic variant within RNF207 is associated with a prolonged QT interval. QT interval prolongation may lead to arrhythmia, a risk factor for sudden cardiac death. Results: RNF207 regulates action potential duration and the repolarizing channel HERG. Conclusion: RNF207 is an important regulator of cardiac excitation. Significance: Understanding the composition and dynamics of membrane complexes is important in unraveling the mechanism of arrhythmias.

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Molecular Genetics of Cardiac Arrhythmias

Wolf

Berul

2010

Encyclopedia of Life Sciences

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Knowledge derived from human genetics and from studies in animal models has led to the discovery of multiple molecular defects underlying inherited arrhythmias and cardiac conduction system diseases in structurally altered or normal hearts. Minor disturbances at the molecular and cellular levels can initiate severe rhythm abnormalities. Some congenital heart diseases and cardiomyopathies carry a higher risk for conduction disturbances or arrhythmias. In the structurally normal heart, inherited cardiac arrhythmias or conduction system disease are most often primary electrical diseases. The underlying molecular defect in those disorders, also termed ion channelopathies, typically involves genes that encode ion channels, responsible for maintaining intracellular and extracellular electrolyte balance. Advances in molecular biology and genetics facilitate the identification of factors that may predispose an individual with or without structural heart disease to arrhythmias or sudden death. Taking those discoveries into clinical practice improves risk stratification and allows potential identification of new therapeutic targets. Key Concepts: Sudden unexpected cardiac death in the pediatric population is a devastating event with an incidence of approximately 1–6 in 100 000 per year and in some cases is the first presentation of a previously undiagnosed disorder. Inherited arrhythmias and cardiac conduction system disease frequently occur in pediatric patients with congenital heart disease but can also be associated with a structurally normal heart. Mutations in genes encoding for cytoskeletal proteins, sarcomeric proteins and ion channels are responsible for the majority of inherited arrhythmias associated with the structurally normal or abnormal heart. Identifying the molecular basis of congenital arrhythmias optimises patient screening, risk stratification and allows genotype‐directed therapies of patients at risk for sudden cardiac death.

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Common variants at ten loci influence QT interval duration in the QTGEN Study

Cited by 392 publications

References 43 publications

The pursuit of genome-wide association studies: where are we now?

The pursuit of genome-wide association studies: where are we now?

RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation

Molecular Genetics of Cardiac Arrhythmias

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