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

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.

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.

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.

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.