Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits
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ABSTRACT:
PROVIDER: PRJNA554117 | ENA |
REPOSITORIES: ENA
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Project description:We conducted a genome-wide analysis to identify regulatory variants affecting the binding of NKX2-5, a core cardiac development transcription factor, and investigated their role in cardiac gene expression and EKG phenotypes. We generated iPSC-derived cardiomyocytes (iPSC-CMs) from a pedigree of seven whole-genome sequenced individuals, and profiled them with a variety of functional genomic assays including RNA-Seq, ATAC-Seq, and ChIP-Seq of both histone modification H3K27ac and NKX2-5. After establishing that iPSC-CMs recapitulated cardiomyocyte-specific expression and epigenetic signatures, and that genetic variants affected the variability of molecular phenotypes across the iPSC-CM lines, we identified heterozygous sites that showed allele-specific effects (ASE). We then investigated NKX2-5 ASE variants in detail by examining whether they altered cardiac TF motifs, and whether they were enriched for eQTLs and EKG GWAS-SNPs. Our data reveal that variation affecting the binding of NKX2-5 and other cardiac TFs likely serves as a molecular mechanism underlying control of numerous EKG loci across the genome, and that fine-mapping approaches, combined with molecular phenotype data from iPSC-CMs, can be used to prioritize causal variants in EKG GWAS loci.
2019-07-12 | GSE133833 | GEO
Project description: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.
| S-EPMC6858543 | biostudies-literature
Project description:Allele-Specific NKX2-5 Binding Underlies Multiple Genetic Associations with Human Electrocardiographic Traits
| PRJNA549750 | ENA
Project description:Mechanisms and disease associations of haplotype-dependent allele specific DNA methylation
| PRJNA315298 | ENA
Project description:Research into the genetic influences of impulsivity and reward motivated behavior relies heavily on outbred animal populations, including Heterogeneous Stock (HS) rats, for the genetic diversity necessary to identify genotype-trait associations. Many such associations have been detected, but it is not always clear which gene or other feature near the identified genomic location is functionally responsible for the association. Since these traits are in part mediated by gene expression, mapping the associations between genotype and gene expression in these animals will enable the discovery and deeper understanding of these trait associations. We therefore obtained genotypes and RNA-Seq gene expression for five brain regions from 88 HS rats and mapped expression quantitative trait loci (eQTLs) for each region. We identified cis-eQTLs in over 3,000 genes per brain region and validated their effect sizes using allele specific expression. This resource will enable new discoveries of the genetic influences of complex behavioral traits.
2021-04-23 | GSE173140 | GEO
Project description:Research into the genetic influences of impulsivity and reward motivated behavior relies heavily on outbred animal populations, including Heterogeneous Stock (HS) rats, for the genetic diversity necessary to identify genotype-trait associations. Many such associations have been detected, but it is not always clear which gene or other feature near the identified genomic location is functionally responsible for the association. Since these traits are in part mediated by gene expression, mapping the associations between genotype and gene expression in these animals will enable the discovery and deeper understanding of these trait associations. We therefore obtained genotypes and RNA-Seq gene expression for five brain regions from 88 HS rats and mapped expression quantitative trait loci (eQTLs) for each region. We identified cis-eQTLs in over 3,000 genes per brain region and validated their effect sizes using allele specific expression. This resource will enable new discoveries of the genetic influences of complex behavioral traits.
2021-04-23 | GSE173139 | GEO
Project description:Research into the genetic influences of impulsivity and reward motivated behavior relies heavily on outbred animal populations, including Heterogeneous Stock (HS) rats, for the genetic diversity necessary to identify genotype-trait associations. Many such associations have been detected, but it is not always clear which gene or other feature near the identified genomic location is functionally responsible for the association. Since these traits are in part mediated by gene expression, mapping the associations between genotype and gene expression in these animals will enable the discovery and deeper understanding of these trait associations. We therefore obtained genotypes and RNA-Seq gene expression for five brain regions from 88 HS rats and mapped expression quantitative trait loci (eQTLs) for each region. We identified cis-eQTLs in over 3,000 genes per brain region and validated their effect sizes using allele specific expression. This resource will enable new discoveries of the genetic influences of complex behavioral traits.
2021-04-23 | GSE173138 | GEO
Project description:Research into the genetic influences of impulsivity and reward motivated behavior relies heavily on outbred animal populations, including Heterogeneous Stock (HS) rats, for the genetic diversity necessary to identify genotype-trait associations. Many such associations have been detected, but it is not always clear which gene or other feature near the identified genomic location is functionally responsible for the association. Since these traits are in part mediated by gene expression, mapping the associations between genotype and gene expression in these animals will enable the discovery and deeper understanding of these trait associations. We therefore obtained genotypes and RNA-Seq gene expression for five brain regions from 88 HS rats and mapped expression quantitative trait loci (eQTLs) for each region. We identified cis-eQTLs in over 3,000 genes per brain region and validated their effect sizes using allele specific expression. This resource will enable new discoveries of the genetic influences of complex behavioral traits.
2021-04-23 | GSE173137 | GEO
Project description:Research into the genetic influences of impulsivity and reward motivated behavior relies heavily on outbred animal populations, including Heterogeneous Stock (HS) rats, for the genetic diversity necessary to identify genotype-trait associations. Many such associations have been detected, but it is not always clear which gene or other feature near the identified genomic location is functionally responsible for the association. Since these traits are in part mediated by gene expression, mapping the associations between genotype and gene expression in these animals will enable the discovery and deeper understanding of these trait associations. We therefore obtained genotypes and RNA-Seq gene expression for five brain regions from 88 HS rats and mapped expression quantitative trait loci (eQTLs) for each region. We identified cis-eQTLs in over 3,000 genes per brain region and validated their effect sizes using allele specific expression. This resource will enable new discoveries of the genetic influences of complex behavioral traits.
2021-04-23 | GSE173136 | GEO
Project description:Atrial specific knockout of Nkx2-5 results in hyperplastic atria with ASD and conduction defects. To examine how Nkx2-5 regulates cardiac proliferation at late gestational stages, RNA-seq was performed. Examination of expression profile of 2 Nkx2-5-null atria and 3 controls
2014-10-31 | E-GEOD-52080 | biostudies-arrayexpress