Cell-type-specific polygenic risk scores reveal adipocyte-related interactions with lipids in coronary artery disease

Background: Genome-wide polygenic risk scores (PRSs) for coronary artery disease (CAD) aggregate genetic effects across the genome and may obscure biologically distinct mechanisms. We aimed to develop cell-type-specific PRSs (csPRSs) using single-cell RNA sequencing (scRNA-seq) data and investigate their interactions with lipids on CAD risk. Methods: Using publicly available scRNA-seq data from human heart tissue, we identified cell-type-specific genes across 13 major cell types and 64 subpopulations and grouped them into 10 cell clusters. Variants from a CAD genome-wide association study (GWAS) were mapped to cluster-specific genes to construct csPRSs for European-ancestry participants from the UK Biobank (UKB). Interactions between csPRSs and lipid-related phenotypes were evaluated using Cox proportional hazards models and stratified analyses, with significant findings further assessed in an internal validation dataset. Results: Distinct interaction patterns with lipid phenotypes were observed across csPRSs. Low-density lipoprotein (LDL)-related lipid traits, including apolipoprotein B (ApoB), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (cholesterol), primarily interacted with adipocytes (Adip), whereas high-density lipoprotein (HDL) traits interacted with endothelial-mesothelial (EC-Meso), fibroblast (FB), and immune-cell csPRSs. Notably, interactions for Adip csPRSs were replicated in internal validation analyses. Conclusions: Cell-type-specific decomposition of genome-wide PRSs for CAD identified biologically distinct lipid interactions that were not captured by the genome-wide PRS. Adipocyte genetic factors may influence how LDL lipids affect CAD risk. These findings highlight the potential of cell-type-informed PRSs to improve the biological interpretation of PRSs and provide insights into the heterogeneous mechanisms underlying CAD.