Discovery of functional variants regulating lipid metabolism in an East Asian population.
BACKGROUND Recent genome-wide association studies have identified more than 900 lipid-related loci; however, the specific genes and mechanisms that regulate blood lipid levels remain incompletely understood. This study aimed to identify lipid-associated variants in Koreans and to investigate their potential functional and regulatory mechanisms. METHODS We performed a genome-wide association study of triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels in 72,298 Korean participants. Genotype data were imputed using the Northeast Asian Reference Database, version 2. We then conducted conditional analysis, statistical fine-mapping, and functional variant-to-gene mapping, and further evaluated the associations of lipid-associated variants with coronary artery disease. Significant variants were subsequently examined using a luciferase reporter assay in HepG2 cells. RESULTS Our analyses identified 182 independent lipid-associated signals, including 64 previously unreported signals. Integrative fine-mapping and variant-to-gene mapping prioritized 24 variants with evidence of transcriptional regulatory effects and 40 linked genes, including potential lipid metabolism regulators PIP5KL1 and UBE4A. Reporter assays further supported allele-specific regulatory activity for rs10987803 and rs5130. Several low-frequency protein-altering variants implicated established lipid metabolism pathways. Notably, a Korean-enriched ANGPTL3 missense variant (rs753849210; p.W338C) was associated with markedly lower triglyceride levels. Lipid effects were directionally concordant with coronary artery disease associations for variants in PCSK9 (rs564427867; p.E32K and rs151193009; p.R93C), HIST1H1C (rs12111009; p.G124A), and CELSR2 (rs77619489; p.A2806V). CONCLUSIONS These findings refine the genetic architecture of lipid traits and nominate candidate genes and regulatory variants for future studies of lipid-related cardiometabolic disease.