TY - JOUR
T1 - Intersecting single-cell transcriptomics and genome-wide association studies identifies crucial cell populations and candidate genes for atherosclerosis
AU - Slenders, Lotte
AU - Landsmeer, Lennart P L
AU - Cui, Kai
AU - Depuydt, Marie A C
AU - Verwer, Maarten
AU - Mekke, Joost
AU - Timmerman, Nathalie
AU - van den Dungen, Noortje A M
AU - Kuiper, Johan
AU - de Winther, Menno P J
AU - Prange, Koen H M
AU - Ma, Wei Feng
AU - Miller, Clint L
AU - Aherrahrou, Redouane
AU - Civelek, Mete
AU - de Borst, Gert J
AU - de Kleijn, Dominique P V
AU - Asselbergs, Folkert W
AU - den Ruijter, Hester M
AU - Boltjes, Arjan
AU - Pasterkamp, Gerard
AU - van der Laan, Sander W
AU - Mokry, Michal
N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Cardiovascular Disease
KW - Genome-Wide Association Study
KW - Single-Cell Analysis
KW - scRNA-seq
UR - https://www.mendeley.com/catalogue/27fa7bf9-c781-30b7-8ab8-2ea5e2a156ed/
U2 - 10.1093/ehjopen/oeab043
DO - 10.1093/ehjopen/oeab043
M3 - Article
C2 - 35174364
SN - 2752-4191
VL - 2
SP - oeab043
JO - European heart journal open
JF - European heart journal open
IS - 1
ER -