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Abstract
Aims
Genome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into biological mechanisms and targets for drug discovery remains challenging. Intersecting genetic and gene expression data has led to the identification of candidate genes. However, previously studied tissues are often non-diseased and heterogeneous in cell composition, hindering accurate candidate prioritization. Therefore, we analysed single-cell transcriptomics from atherosclerotic plaques for cell-type-specific expression to identify atherosclerosis-associated candidate gene–cell pairs.
Methods and results
We applied gene-based analyses using GWAS summary statistics from 46 atherosclerotic and cardiovascular disease, risk factors, and other traits. We then intersected these candidates with single-cell RNA sequencing (scRNA-seq) data to identify genes specific for individual cell (sub)populations in atherosclerotic plaques. The coronary artery disease (CAD) loci demonstrated a prominent signal in plaque smooth muscle cells (SMCs) (SKI, KANK2, and SORT1) P-adj. = 0.0012, and endothelial cells (ECs) (SLC44A1, ATP2B1) P-adj. = 0.0011. Finally, we used liver-derived scRNA-seq data and showed hepatocyte-specific enrichment of genes involved in serum lipid levels.
Conclusion
We discovered novel and known gene–cell pairs pointing to new biological mechanisms of atherosclerotic disease. We highlight that loci associated with CAD reveal prominent association levels in mainly plaque SMC and EC populations. We present an intuitive single-cell transcriptomics-driven workflow rooted in human large-scale genetic studies to identify putative candidate genes and affected cells associated with cardiovascular traits. Collectively, our workflow allows for the identification of cell-specific targets relevant for atherosclerosis and can be universally applied to other complex genetic diseases and traits.
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Details
1 Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands
2 Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
3 Department of Vascular Surgery, University Medical Centre Utrecht, University Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands
4 Department of Medical Biochemistry, Amsterdam University Medical Centers—Location AMC, University of Amsterdam, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, The Netherlands
5 Medical Scientist Training Program, University of Virginia, 200 Jeanette Lancaster Way, Charlottesville, VA 22908, USA; Center for Public Health Genomics, University of Virginia, West Complex, 1335 Lee St, Charlottesville, VA 22908, USA
6 Center for Public Health Genomics, University of Virginia, West Complex, 1335 Lee St, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Rark Avenue, Charlottesville, VA 22908, USA; Department of Public Health Sciences, University of Virginia, West Complex Rm 3181, Charlottesville, VA 22908, USA
7 Center for Public Health Genomics, University of Virginia, West Complex, 1335 Lee St, Charlottesville, VA 22908, USA
8 Center for Public Health Genomics, University of Virginia, West Complex, 1335 Lee St, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, VA 22908, USA
9 Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Heidelberglaan 100, Utrecht 3508 GA, The Netherlands
10 Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands; Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Heidelberglaan 100, Utrecht 3508 GA, The Netherlands