Intersecting single-cell transcriptomics and genome-wide association studies identifies crucial cell populations and candidate genes for atherosclerosis

Lotte Slenders, Lennart P L Landsmeer, Kai Cui, Marie A C Depuydt, Maarten Verwer, Joost Mekke, Nathalie Timmerman, Noortje A M van den Dungen, Johan Kuiper, Menno P J de Winther, Koen H M Prange, Wei Feng Ma, Clint L Miller, Redouane Aherrahrou, Mete Civelek, Gert J de Borst, Dominique P V de Kleijn, Folkert W Asselbergs, Hester M den Ruijter, Arjan BoltjesGerard Pasterkamp, Sander W van der Laan, Michal Mokry

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)oeab043
JournalEuropean heart journal open
Volume2
Issue number1
Early online date21 Dec 2021
DOIs
Publication statusPublished - Jan 2022
Externally publishedYes

Keywords

  • Atherosclerosis
  • Cardiovascular Disease
  • Genome-Wide Association Study
  • Single-Cell Analysis
  • scRNA-seq

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