ArticleAmerican journal of human genetics2014
An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.Circulation. Genomic and precision medicine · 2018Pooled it
- A novel machine learning-based algorithm for eQTL identification reveals complex pleiotropic effects in the MHC region.Briefings in bioinformatics · 2026Article
- Mapping cardiac electrical abnormalities in rodents.Physiological genomics · 2025Article
- Identification and Functional Assessment of Candidate CausalCirculation. Genomic and precision medicine · 2025Article
- Massively parallel reporter assays identify functional enhancer variants at QT interval GWAS loci.bioRxiv : the preprint server for biology · 2025Article
- Twenty-first century mouse genetics is again at an inflection point.Lab animal · 2025Review
- A comprehensive in silico investigation into the pathogenic SNPs in the RTEL1 gene and their biological consequences.PloS one · 2024Article
- Cardiac muscle-restricted partial loss of Nos1ap expression has limited but significant impact on electrocardiographic features.G3 (Bethesda, Md.) · 2023Article
- The intercalated disc: a unique organelle for electromechanical synchrony in cardiomyocytes.Physiological reviews · 2023Review
- The Advantages, Challenges, and Future of Human-Induced Pluripotent Stem Cell Lines in Type 2 Long QT Syndrome.Journal of cardiovascular translational research · 2023Review
- Investigation of UTR Variants by Computational Approaches Reveal Their Functional Significance inGenes · 2023Article
- Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram.Nature cardiovascular research · 2023Article
- Construction of a transposase accessible chromatin landscape reveals chromatin state of repeat elements and potential causal variant for complex traits in pigs.Journal of animal science and biotechnology · 2022Article
- A comparative investigation on H3K27ac enhancer activities in the brain and liver tissues between wild boars and domesticated pigs.Evolutionary applications · 2022Article
- Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity.Nature genetics · 2022Article
- Article
- Multidisciplinary approaches for elucidating genetics and molecular pathogenesis of urinary tract malformations.Kidney international · 2022Review
- The role of pharmacogenomics in contemporary cardiovascular therapy: a position statement from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.European heart journal. Cardiovascular pharmacotherapy · 2022Article
- Genomic enhancers in cardiac development and disease.Nature reviews. Cardiology · 2022Review
- Structural and functional analysis of somatic coding and UTR indels in breast and lung cancer genomes.Scientific reports · 2021Article
Corrections and comments
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Authors and funding
23 authors at 10 institutions in 4 countries.
Funding
Abstract
QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.
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Registered trials
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