Intersecting single-cell transcriptomics and genome-wide association studies identifies crucial cell populations and candidate genes for atherosclerosis
European Heart Journal Open, vol. 2, pp. oeab043
Abstract
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.
Authors 23
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Affiliation as printed
Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University , Einsteinweg 55 , 2333 CC Leiden, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Department of Medical Biochemistry, Amsterdam University Medical Centers—Location AMC, University of Amsterdam, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences , Meibergdreef 9 , Amsterdam, The Netherlands
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Affiliation as printed
Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University , Einsteinweg 55 , 2333 CC Leiden, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Department of Medical Biochemistry, Amsterdam University Medical Centers—Location AMC, University of Amsterdam, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences , Meibergdreef 9 , Amsterdam, The Netherlands
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Affiliation as printed
Center for Public Health Genomics, University of Virginia , West Complex, 1335 Lee St, Charlottesville, VA 22908, USA
Medical Scientist Training Program, University of Virginia , 200 Jeanette Lancaster Way, Charlottesville, VA 22908, USA
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Affiliation as printed
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
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Affiliation as printed
Center for Public Health Genomics, University of Virginia , West Complex, 1335 Lee St, Charlottesville, VA 22908, USA
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Affiliation as printed
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
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , Utrecht 3508 GA, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , Utrecht 3508 GA, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Sander W. van der Laan corresponding
Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, University Utrecht , Heidelberglaan 100 , 3508 GA Utrecht, The Netherlands
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Michal Mokrý corresponding
Utrecht University · University Medical Center Utrecht
Affiliation as printed
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
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