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Aortic Cellular Diversity and Quantitative GWAS Trait Prioritization through Single Nuclear RNA Sequencing (snRNA-Seq) of the Aneurysmal Human Aorta

ABSTRACT: Aortic Cellular Diversity and Quantitative GWAS Trait Prioritization through Single Nuclear RNA Sequencing (snRNA-Seq) of the Aneurysmal Human Aorta

PROVIDER: PRJNA857062 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20053727.fastq.gz	Fastqsanger.gz
	SRR20053728.fastq.gz	Fastqsanger.gz
	SRR20053729.fastq.gz	Fastqsanger.gz
	SRR20053730.fastq.gz	Fastqsanger.gz
	SRR20053731.fastq.gz	Fastqsanger.gz

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Project description:BackgroundMural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue.MethodsSingle-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data.ResultsWe sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes JUN, LTBP4 (latent transforming growth factor beta-binding protein 1), and IL34 (interleukin 34) in fibroblasts, ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4), and GLRX in vascular smooth muscle cells, as well as LRP1 in macrophage populations.ConclusionsUsing nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.

Dataset Information

Aortic Cellular Diversity and Quantitative GWAS Trait Prioritization through Single Nuclear RNA Sequencing (snRNA-Seq) of the Aneurysmal Human Aorta

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