Seppo Ylä-Herttuala (Finland)
University of Eastern Finland A.I.Virtanen InstituteAuthor Of 1 Presentation
O047 - Functional fine-mapping of coronary artery disease risk variants identified by single-cell profiling of accessible chromatin in human atherosclerotic lesions (ID 195)
Abstract
Background and Aims
Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD). Many of these loci are enriched in cis-regulatory elements (CREs) but not linked to cardiometabolic risk factors nor to candidate causal genes, complicating their functional interpretation.
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 primary human aortic endothelial cells and STARR-Seq massively parallel reporter assay in smooth muscle cells. This analysis identified potential causal SNP(s) and the associated target gene for over 30 CAD loci. We present several examples where the chromatin accessibility and gene expression could be assigned to one cell type predicting the cell type of action for CAD loci.
Conclusions
These findings highlight the potential of applying snATAC-seq to human tissues in revealing relative contributions of distinct cell types to diseases and in identifying genes likely to be influenced by non-coding GWAS variants.