Partitioning heritability using single-cell multi-omics identifies a novel macrophage subpopulation conveying genetic risks of coronary artery disease

Abstract

AbstractBackgroundCoronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. While over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types like macrophages.MethodsWe utilized single-cell RNA-seq (scRNA-seq) and single-cell multi-omics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis—the formation of lipid-laden foam cells. Meta-analysis of scRNA-seq datasets from 26 human plaque samples was undertaken to provide a comprehensive atlas of lesional macrophages and to correlate subpopulationsin vivoandex vivo. The genetic risk levels of CAD were assessed by partitioning disease heritability across different macrophage subpopulations.ResultsWe identified a novel macrophage subpopulation, termed lipid-handling macrophages, bothex vivoandin vivo, and identified associated marker genes, transcription regulators, and functional pathways. 18,782 cis-regulatory elements were identified by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD GWAS data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of lipid-handling macrophages. We investigated the cis-regulatory effect of a risk variant rs10488763 onFDX1,implicating the recruitment of AP-1 and C/EBP-beta in the causal mechanisms at this locus.ConclusionsOur results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key sub-population through which genetic variants actively influence disease. These findings provide an unbiased framework for functional fine-mapping of GWAS results using single-cell multi-omics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.