ArticleNature genetics2019
Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits.
Article in Nature genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- Article
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Sequence and parent-of-origin dependent mThe EMBO journal · 2025Article
- Dissecting cardiovascular disease-associated noncoding genetic variants using human iPSC models.Stem cell reports · 2025Review
- Multiomic QTL mapping reveals phenotypic complexity of GWAS loci and prioritizes putative causal variants.Cell genomics · 2025Article
- IFNγ activates an immune-like regulatory network in the cardiac vascular endothelium.Journal of molecular and cellular cardiology plus · 2025Article
- Current advances in human-induced pluripotent stem cell-based models and therapeutic approaches for congenital heart disease.Molecular and cellular biochemistry · 2025Review
- Multiome-wide Association Studies: Novel Approaches for Understanding Diseases.Genomics, proteomics & bioinformatics · 2024Review
- Multicohort Epigenome-Wide Association Study of All-Cause Cardiovascular Disease and Cancer Incidence: A Cardio-Oncology Approach.JACC. CardioOncology · 2024Article
- Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses.iScience · 2024Article
- Genetics, transcriptomics, metagenomics, and metabolomics in the pathogenesis and prediction of atrial fibrillation.European heart journal supplements : journal of the European Society of Cardiology · 2024Article
- Stem cell models of inherited arrhythmias.Nature cardiovascular research · 2024Review
- Decoding Non-coding Variants: Recent Approaches to Studying Their Role in Gene Regulation and Human Diseases.Frontiers in bioscience (Scholar edition) · 2024Review
- Complex regulatory networks influence pluripotent cell state transitions in human iPSCs.Nature communications · 2024Article
- Atrial fibrillation: pathophysiology, genetic and epigenetic mechanisms.The Lancet regional health. Europe · 2024Review
- Prioritizing cardiovascular disease-associated variants altering NKX2-5 and TBX5 binding through an integrative computational approach.The Journal of biological chemistry · 2023Article
- Single-nucleotide variants within heart enhancers increase binding affinity and disrupt heart development.Developmental cell · 2023Article
- Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation.Nature communications · 2023Article
- Disease-associated non-coding variants alter NKX2-5 DNA-binding affinity.Biochimica et biophysica acta. Gene regulatory mechanisms · 2023Article
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 2 countries.
Funding
Abstract
The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.