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Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224997 | GEO | 2023/02/10

REPOSITORIES: GEO

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Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation.

Project description:Genome-wide association studies (GWAS) have linked hundreds of loci to cardiac diseases. However, in most loci the causal variants and their target genes remain unknown. We developed a combined experimental and analytical approach that integrates single cell epigenomics with GWAS to prioritize risk variants and genes. We profiled accessible chromatin in single cells obtained from human hearts and leveraged the data to study genetics of Atrial Fibrillation (AF), the most common cardiac arrhythmia. Enrichment analysis of AF risk variants using cell-type-resolved open chromatin regions (OCRs) implicated cardiomyocytes as the main mediator of AF risk. We then performed statistical fine-mapping, leveraging the information in OCRs, and identified putative causal variants in 122 AF-associated loci. Taking advantage of the fine-mapping results, our novel statistical procedure for gene discovery prioritized 46 high-confidence risk genes, highlighting transcription factors and signal transduction pathways important for heart development. In summary, our analysis provides a comprehensive map of AF risk variants and genes, and a general framework to integrate single-cell genomics with genetic studies of complex traits.

| S-EPMC10435551 | biostudies-literature

Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation [scATAC-seq]

Project description:Genome-wide association studies (GWAS) have linked hundreds of loci to cardiac diseases. However, in most loci the causal variants and their target genes remain unknown. We developed a combined experimental and analytical approach that integrates single cell epigenomics with GWAS to prioritize risk variants and genes. We profiled accessible chromatin in single cells obtained from human hearts and leveraged the data to study genetics of Atrial Fibrillation (AF), the most common cardiac arrhythmia. Enrichment analysis of AF risk variants using cell-type-resolved open chromatin regions (OCRs) implicated cardiomyocytes as the main mediator of AF risk. We then performed statistical fine-mapping, leveraging the information in OCRs, and identified putative causal variants in 122 AF-associated loci. Taking advantage of the fine-mapping results, our novel statistical procedure for gene discovery prioritized 45 high-confidence risk genes, highlighting transcription factors and signal transduction pathways important for heart development. We further leveraged our single-cell data to study genetics of gene expression. An unexpected finding from earlier studies is that expression QTLs (eQTLs) are often shared across tissues even though most regulatory elements are cell-type specific. We found that this sharing is largely driven by the limited power of eQTL studies using bulk tissues to detect cell-type-specific regulatory variants. This finding points to an important limitation of using eQTLs to interpret GWAS of complex traits. In summary, our analysis provides a comprehensive map of AF risk variants and genes, and a general framework to integrate single-cell genomics with genetic studies of complex traits.

2023-02-12 | GSE224996 | GEO

Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation [snRNA-seq]

Project description:Genome-wide association studies (GWAS) have linked hundreds of loci to cardiac diseases. However, in most loci the causal variants and their target genes remain unknown. We developed a combined experimental and analytical approach that integrates single cell epigenomics with GWAS to prioritize risk variants and genes. We profiled accessible chromatin in single cells obtained from human hearts and leveraged the data to study genetics of Atrial Fibrillation (AF), the most common cardiac arrhythmia. Enrichment analysis of AF risk variants using cell-type-resolved open chromatin regions (OCRs) implicated cardiomyocytes as the main mediator of AF risk. We then performed statistical fine-mapping, leveraging the information in OCRs, and identified putative causal variants in 122 AF-associated loci. Taking advantage of the fine-mapping results, our novel statistical procedure for gene discovery prioritized 45 high-confidence risk genes, highlighting transcription factors and signal transduction pathways important for heart development. We further leveraged our single-cell data to study genetics of gene expression. An unexpected finding from earlier studies is that expression QTLs (eQTLs) are often shared across tissues even though most regulatory elements are cell-type specific. We found that this sharing is largely driven by the limited power of eQTL studies using bulk tissues to detect cell-type-specific regulatory variants. This finding points to an important limitation of using eQTLs to interpret GWAS of complex traits. In summary, our analysis provides a comprehensive map of AF risk variants and genes, and a general framework to integrate single-cell genomics with genetic studies of complex traits.

2023-02-12 | GSE224995 | GEO

Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation

Project description:Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation

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Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation [snRNA-seq]

Project description:Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation [snRNA-seq]

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Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation [scATAC-seq]

Project description:Single-cell genomics improves the discovery of risk variants and genes of Atrial Fibrillation [scATAC-seq]

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Genomics of Atrial Fibrillation.

Project description:Atrial fibrillation (AF) is a common clinical arrhythmia that appears to be highly heritable, despite representing a complex interplay of several disease processes that generally do not manifest until later in life. In this manuscript, we will review the genetic basis of this complex trait established through studies of familial AF, linkage and candidate gene studies of common AF, genome wide association studies (GWAS) of common AF, and transcriptomic studies of AF. Since AF is associated with a five-fold increase in the risk of stroke, we also review the intersection of common genetic factors associated with both of these conditions. Similarly, we highlight the intersection of common genetic markers associated with some risk factors for AF, such as hypertension and obesity, and AF. Lastly, we describe a paradigm where genetic factors predispose to the risk of AF, but which may require additional stress and trigger factors in older age to allow for the clinical manifestation of AF.

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Identification of Atrial Fibrillation associated genes and functional non-coding variants

Project description:Expression analysis of whole tissue and cardiomyocytes of fetal and adult atrial free wall

2019-10-29 | GSE127856 | GEO

Single-cell profile of atrial human fibroblasts in cardiac arrhythmia atrial fibrillation

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-10 | GSE148507 | GEO

FOG2 modulates a TBX5/GATA4-co-ocupied atrial gene regulatory network linking heart failure to atrial fibrillation risk

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-02 | GSE198788 | GEO