Related Papers
Journal of Clinical Investigation
Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer
2012 •
Federico Tessadori
Circulation: Cardiovascular Genetics
Genetic Determinants of P Wave Duration and PR Segment
2014 •
Malou van den Boogaard
Background— The PR interval on the ECG reflects atrial depolarization and atrioventricular nodal delay which can be partially differentiated by P wave duration and PR segment, respectively. Genome-wide association studies have identified several genetic loci for PR interval, but it remains to be determined whether this is driven by P wave duration, PR segment, or both. Methods and Results— We replicated 7 of the 9 known PR interval loci in 16 468 individuals of European ancestry. Four loci were unambiguously associated with PR segment, while the others were shared for P wave duration and PR segment. Next, we performed a genome-wide analysis on P wave duration and PR segment separately and identified 5 novel loci. Single-nucleotide polymorphisms in KCND3 ( P =8.3×10 –11 ) and FADS2 ( P =2.7×10 –8 ) were associated with P wave duration, whereas single-nucleotide polymorphisms near IL17D (P =2.3×10 –8 ), in EFHA1 ( P =3.3×10 −10 ), and in LRCH1 ( P =2.1×10 –8 ) were associated with PR ...
Allele-specific NKX2-5 binding underlies multiple genetic associations with human EKG traits
Sanghamitra Singhal
Genetic variation affecting the binding of transcription factors (TFs) has been proposed as a major mechanism underlying susceptibility to common disease. NKX2-5, a key cardiac development TF, has been associated with electrocardiographic (EKG) traits through GWAS, but the extent to which differential binding of NKX2-5 contributes to these traits has not yet been studied. Here, we analyzed transcriptomic and epigenomic data generated from iPSC-derived cardiomyocyte lines (iPSC-CMs) from seven whole- genome sequenced individuals in a three-generational family. We identified ~2,000 single nucleotide variants (SNVs) associated with allele-specific effects (ASE) on NKX2-5 binding. These ASE-SNVs were enriched for altered TF motifs (both cognate and other cardiac TFs), and were positively correlated with changes in H3K27ac in iPSC-CMs, suggesting they impact cardiac enhancer activity. We found that NKX2- 5 ASE-SNVs were significantly enriched for being heart-specific eQTLs and EKG GWAS v...
Cold Spring Harbor perspectives in medicine
Genetic networks governing heart development
2014 •
Richard J Harvey
Animal genomes contain a code for construction of the body plan from a fertilized egg. Understanding how genome information is deciphered to create the complex multilayered regulatory systems that drive organismal development, and which become altered in disease, is one of the greatest challenges in the biological sciences. The development of methods that effectively represent and communicate the complexity inherent in gene regulatory networks remains a major barrier. This review introduces the philosophy of systems biology and discusses recent progress in understanding the development of the heart at a systems biology level.
International Journal of Molecular Sciences
Role of Non-Coding Variants in Brugada Syndrome
Sara Pagans
Brugada syndrome (BrS) is an inherited electrical heart disease associated with a high risk of sudden cardiac death (SCD). The genetic characterization of BrS has always been challenging. Although several cardiac ion channel genes have been associated with BrS, SCN5A is the only gene that presents definitive evidence for causality to be used for clinical diagnosis of BrS. However, more than 65% of diagnosed cases cannot be explained by variants in SCN5A or other genes. Therefore, in an important number of BrS cases, the underlying mechanisms are still elusive. Common variants, mostly located in non-coding regions, have emerged as potential modulators of the disease by affecting different regulatory mechanisms, including transcription factors (TFs), three-dimensional organization of the genome, or non-coding RNAs (ncRNAs). These common variants have been hypothesized to modulate the interindividual susceptibility of the disease, which could explain incomplete penetrance of BrS observ...
Circulation Research
Transcriptional Patterning of the Ventricular Cardiac Conduction System
2020 •
Ozanna Ozii Burnicka-Turek
Journal of Clinical Investigation
TBX5 drives Scn5a expression to regulate cardiac conduction system function
2012 •
John Fahrenbach
Journal of Molecular and Cellular Cardiology
Common genetic variation modulating cardiac ECG parameters and susceptibility to sudden cardiac death
2012 •
Michael Tanck
Nature Communications
NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network
2018 •
Elizabeth Qian
Journal of the American Heart Association
Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes
2016 •
Wataru Shimizu
Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias. We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patien...
