Functional fine-mapping of coronary artery disease risk variants identified by single-cell profiling of accessible chromatin in human atherosclerotic lesions

摘要: Methods: We investigated chromatin accessibility profiles of the human atherosclerotic lesions using single nucleus (sn) ATAC-Seq to map cell type-specific patterns of CREs, to understand transcription factors establishing cell identity and to interpret CAD-relevant, non-coding genetic variation.Results: We identified specific transcription factors associated with macrophage subtypes and the differentiation trajectory of smooth muscle cells transitioning into fibromyocytes. We demonstrate that endothelial and smooth muscle cell enhancers are particularly enriched for blood pressure and CAD associated genetic variants. We prioritized putative target genes and candidate regulatory elements for∼ 30% of all the CAD loci using single cell co-accessibility and cis-eQTL information. Finally, we performed genome-wide experimental fine-mapping of the CAD GWAS variants using epigenetic molecular QTL analysis in …