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Mapping genes to cardiovascular susceptibility loci at a single-cell resolution
To date, genome-wide association studies (GWAS) have identified hundreds of risk loci for coronary artery disease (CAD), and other cardiometabolic diseases and traits. However, identifying the key genes for atherosclerotic disease in these loci remains challenging. Here, we systematically mapped 14 GWAS and leveraged transcriptomics of advanced atherosclerotic plaques (AP) at a single-cell resolution.
We isolated viable, nucleated single-cells from plaques of 3 carotid endarterectomy patients using enzymatic digestion and fluorescence-activated cell sorting. We applied a CEL-seq2/SORT-seq protocol and the Seurat pipeline for single-cell RNA sequencing (scRNAseq) and cell identification, respectively. Next we annotated public GWAS data of cardiovascular diseases, and cardiometabolic traits using FUMA, which is based on LD clumping, physical location, regulatory and transcriptomic data.
Using scRNAseq we identified 11 cellular clusters in AP, and integrated these data...
Show moreTo date, genome-wide association studies (GWAS) have identified hundreds of risk loci for coronary artery disease (CAD), and other cardiometabolic diseases and traits. However, identifying the key genes for atherosclerotic disease in these loci remains challenging. Here, we systematically mapped 14 GWAS and leveraged transcriptomics of advanced atherosclerotic plaques (AP) at a single-cell resolution.
We isolated viable, nucleated single-cells from plaques of 3 carotid endarterectomy patients using enzymatic digestion and fluorescence-activated cell sorting. We applied a CEL-seq2/SORT-seq protocol and the Seurat pipeline for single-cell RNA sequencing (scRNAseq) and cell identification, respectively. Next we annotated public GWAS data of cardiovascular diseases, and cardiometabolic traits using FUMA, which is based on LD clumping, physical location, regulatory and transcriptomic data.
Using scRNAseq we identified 11 cellular clusters in AP, and integrated these data to map 1,336 loci across 14 cardiometabolic GWAS. For CAD 105 mapped genes in 35 established loci were differentially expressed between cellular clusters. Some of these loci harboured upto 10 differentially expressed genes, highly expressed in endothelial cells, mast cells, and smooth muscle cells. Notably, some CAD genes are almost exclusively expressed in a specific cell: in the NOS3 locus, KCNH2 is highly expressed in mast cells, whereas NOS3 itself, but also AMPD2 (SORT1 locus) are highly expressed in endothelial cells.
We systematically mapped and annotated risk loci, and integrated this at a single-cell resolution with transcriptomics from AP. We identified specific genes and cellular clusters relevant to atherosclerotic plaques development and progression, informative for future mechanistic studies.
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- Laan, S.W. van der; Slenders, L.; Depuydt, M.; Prange, K.; Granneman, L.; Elbersen, D.; Boltjes, A.; Jager, S. de; Slutter, B.; Bot, I.; Winther, M.; Kuiper, J.; Mokry, M.; Asselbergs, F.; Pasterkamp, G.
- Date
- 2019-08-31
- Volume
- 287
- Pages
- E21 - E21