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Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses (bulk RNA-seq)

ABSTRACT: Atrial fibrillation (AF) is the most common arrhythmia in the world, and is linked to significant morbidity and mortality. Despite advances in the treatment and management of AF, important challenges remain for patients. Human genetics can provide strong therapeutic candidates, but the identification of the causal genes and their functions is difficult. Here, we apply an AF fine-mapping strategy that leverages results from a cross-ancestry genome-wide association study (GWAS), expression quantitative trait loci (eQTLs) from left atrial appendages (LAA) obtained from two cohorts with distinct ancestry (European and East Asian), and a paired RNAseq and ATACseq LAA single-nucleus assay (sn-multiome). We found that AF-associated LAA eQTLs are largely consistent across ancestries. At ten AF loci, our co-localization and fine-mapping analyses implicated 14 genes. Furthermore, by integrating our LAA sn-multiome data and other epigenomic datasets with our fine-mapping results, we identified four primary candidate causal AF variants, including rs7612445 at GNB4 and rs242557 at MAPT, for which we propose molecular mechanisms of AF-association at the cellular level. Finally, we showed that the repression of the strongest AF-associated eQTL gene, LINC01629, in human embryonic stem cell-derived cardiomyocytes using CRISPR inhibition results in the dysregulation of pathways linked to genes involved in the development of atrial tissue and the cardiac conduction system (e.g. HCN4, PITX2 and TBX5).

ORGANISM(S): Homo sapiens

PROVIDER: GSE271839 | GEO | 2024/07/09

REPOSITORIES: GEO

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Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses

Project description:Atrial fibrillation (AF) is the most common arrhythmia in the world, and is linked to significant morbidity and mortality. Despite advances in the treatment and management of AF, important challenges remain for patients. Human genetics can provide strong therapeutic candidates, but the identification of the causal genes and their functions is difficult. Here, we apply an AF fine-mapping strategy that leverages results from a cross-ancestry genome-wide association study (GWAS), expression quantitative trait loci (eQTLs) from left atrial appendages (LAA) obtained from two cohorts with distinct ancestry (European and East Asian), and a paired RNAseq and ATACseq LAA single-nucleus assay (sn-multiome). We found that AF-associated LAA eQTLs are largely consistent across ancestries. At ten AF loci, our co-localization and fine-mapping analyses implicated 14 genes. Furthermore, by integrating our LAA sn-multiome data and other epigenomic datasets with our fine-mapping results, we identified four primary candidate causal AF variants, including rs7612445 at GNB4 and rs242557 at MAPT, for which we propose molecular mechanisms of AF-association at the cellular level. Finally, we showed that the repression of the strongest AF-associated eQTL gene, LINC01629, in human embryonic stem cell-derived cardiomyocytes using CRISPR inhibition results in the dysregulation of pathways linked to genes involved in the development of atrial tissue and the cardiac conduction system (e.g. HCN4, PITX2 and TBX5).

2024-07-09 | GSE238242 | GEO

Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

Project description:Background: Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess whether this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation. Methods: mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAA) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n=83) or in LAA cardiomyocytes (n=52), and combined with clinical parameters to predict AF recurrence. Literature suggests bone morphogenetic protein 10 (BMP10) as a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with eleven cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients. Results: Reduced cardiomyocyte PITX2 concentrations, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(ΔΔCt) increase in PITX2). RNA sequencing, qPCR and Western blotting confirmed BMP10 as one of most PITX2-repressed atrial genes. Left atrial size (hazard ratio per mm increase, HR [95%CI] 1.055 [1.028, 1.082], non-paroxysmal AF (HR 1.672 [1.206, 2.318]) and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed eleven other cardiovascular biomarkers in predicting recurrent AF. Conclusions: Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted, atrial protein BMP10 identify patients at risk of recurrent AF after ablation.

2020-06-19 | GSE152181 | 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 [scATAC-seq]

2023-02-12 | GSE224996 | GEO

Region-specific gene expression profiles in left atria of patients with valvular atrial fibrillation

Project description:Of 54,675 expressed sequence tags, microarray analysis revealed that 391 genes were differently expressed (>1.5-fold difference) between LA-PV junction and LAA, including genes related to arrhythmia, cell death, fibrosis, hypertrophy, and inflammation. Microarray and q-PCR produced parallel results in analyzing the expression of particular genes. The expression of paired like homeodomain-2 (PITX2) and its target protein (short stature homeobox-2 [SHOX2]) was greater in LA-PV junction than in LAA, which may contribute to arrhythmogenesis. Five genes related to thrombogenesis were up-regulated in LAA, which may implicate for the preferential thrombus formation in LAA. Genes related to fibrosis were highly expressed in LAA, which was reflected by intense ultrastructural changes in this region Paired LA-PV junction and left atrial appendage (LAA) specimens were obtained from 16 patients with persistent AF receiving valvular surgery. The Paired specimens were sent for microarray comparison. Selected results were validated by quantitative real time-PCR (q-PCR) and Western blotting. Ultrastructural changes in the atria were evaluated by immunohistochemistry.

2013-09-18 | E-GEOD-41177 | biostudies-arrayexpress

African American hepatocyte genotype

Project description:African Americans (AAs) are disproportionately affected by metabolic diseases and adverse drug events, with limited publicly available genomic and transcriptomic data to advance the knowledge of the molecular underpinnings or genetic associations to these diseases or drug response phenotypes. To fill this gap, we obtained 60 primary hepatocyte cultures from AA liver donors for genome-wide mapping of expression quantitative trait loci (eQTL) using LAMatrix. We identified 277 eGenes and 19,770 eQTLs, of which 67 eGenes and 7,415 eQTLs are not observed in the Genotype-Tissue Expression Project (GTEx) liver eQTL analysis. Of the eGenes found in GTEx only 25 share the same lead eQTL. These AA-specific eQTLs are less correlated to GTEx eQTL in effect sizes and have larger Fst values compared to eQTLs found in both cohorts (overlapping eQTLs). We assessed the overlap between GWAS variants and their tagging variants with AA hepatocyte eQTLs and demonstrated that AA hepatocyte eQTLs can decrease the number of potential causal variants at GWAS loci. Additionally, we identified 75,002 exon QTLs of which 48.8% are not eQTLs in AA hepatocytes. Our analysis provides the first comprehensive characterization of AA hepatocyte eQTLs and highlights the unique discoveries that are made possible due to the increased genetic diversity within the African ancestry genome.

2020-03-27 | GSE147628 | GEO

Atrial fibrillation is associated with altered left-to-right atria gene expression ratio: implications for arrhythmogenesis and thrombogenesis

Project description:Background: Atrial fibrillation (AF) causes atrial remodeling, and the left atrium (LA) is the favored substrate for maintaining AF. However, it remains unclear if AF remodels both atria differently and contributes to LA arrhythmogenesis and thrombogenesis. Results: AF was associated with differential LA-to-RA gene expression related to specific ion channels and pathways as well as upregulation of thrombogenesis-related genes in the LA appendage. Targeting the molecular mechanisms underlying the LA-to-RA difference and AF-related remodeling in the LA appendage may help provide new therapeutic options in treating AF and preventing thromboembolism in AF. Paired left atrial and right atrial specimens were obtained from 13 patients with persistent AF receiving valvular surgery. The Paired specimens were sent for microarray comparison. Selected results were validated by quantitative real time-PCR (q-PCR) and Western blotting. Ultrastructural changes in the atria were evaluated by immunohistochemistry.

2016-08-09 | E-GEOD-79768 | biostudies-arrayexpress

Global peripheral blood gene expression study and trans-eQTLs [HumanHT-12 V3.0]

Project description:The objective of this analysis was to identify trans-eQTLs. Samples were collected from control participants of the Heart and Vascular Health (HVH) study that constitutes a group of population based case control studies of myocardial infarction (MI), stroke, venous thromboembolism (VTE), and atrial fibrillation (AF) conducted among 30-79 year old members of Group Health, a large integrated health care organization in Washington State. Total RNA was isolated from peripheral collected using PAXgene tubes and gene expression was profiled using the Illumina platform.

2013-06-08 | E-GEOD-47727 | biostudies-arrayexpress

Global peripheral blood gene expression study and trans-eQTLs [HumanHT-12 V4.0]

2013-06-08 | E-GEOD-47728 | biostudies-arrayexpress

Titin-dependent transient ventricular defects result in adult atrial arrhythmia and impaired contractility

Project description:Atrial fibrillation (AF), the most common arrhythmia, is occasionally associated with cardiac developmental defects, but causal relationships are poorly defined. Importantly, functional compensation for developmental defects may mask increased risk of arrhythmia in adults. Here, we deleted 9 amino acids (Δ9) within a highly conserved A-band region of titin, a giant protein that serves as a molecular spring in cardiomyocytes, in both zebrafish and human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that the cardiac morphology of ttnaΔ9/Δ9 homozygous zebrafish embryos is perturbed and accompanied by reduced functional output, but ventricular function recovers within a few days of embryonic development, with most embryos reaching adulthood. Despite normal ventricular function, ttnaΔ9/Δ9 adults exhibit AF and atrial cardiomyopathy, with a striking absence of fibrosis, and these findings are recapitulated in TTNΔ9/Δ9-hiPSC-aCMs. Electrophysiological and proteomics analyses reveal atrial action potential shortening and increased expression and function of the cardiac potassium channel Kv7.1 and the slow delayed rectifier potassium current (IKs). Pharmacological suppression of IKs in both models prevents AF and improves atrial contractility. Collectively, these findings reveal how a small internal deletion in a large structural protein causes developmental abnormalities that functionally recover but increase the risk of adult cardiac disease via ion channel remodeling. The observed rescue with targeted antiarrhythmic therapy may have broader implications for the treatment of patients who harbor disease-causing rare variants in sarcomeric proteins.

2024-08-09 | PXD038300 | Pride

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