Large-scale genome-wide associations comprising multiple studies have identified hundreds of genetic loci commonly associated with hyperlipidemia-related phenotypes. However, single large cohort remains necessary in aiming to investigate ethnicity-specific genetic risks and mechanical insights. A community-based cohort comprising 23,988 samples that included both genotype and biochemical information was assembled for the genome-wide association analysis (GWAS) of hyperlipidemia. The analysis identified fifty genetic variants (P < 5 × 10−8) on five different chromosomes, and a subsequent validation analysis confirmed the significance of the lead variants. Integrated analysis combined with cell-based experiments of the most statistically significant locus in 11q23.3 revealed rs651821 (P = 4.52 × 10−76) as the functional variant. We showed transcription factor GATA4 preferentially binds the T allele of rs651821, the protective allele for hyperlipidemia, which promoted APOA5 expression in liver cells and individuals with the TT genotype of rs651821. As GATA4-APOA5 axis maintains triglyceride homeostasis, GATA4 activation by phenylephrine implies synergism for lowering triglyceride levels in hyperlipidemia patients. Our study demonstrates that rs651821 mediates APOA5 activation via allele-specific regulation by GATA4. We suggest elevating GATA4 activity could provide a therapeutic potential for treating the development of hyperlipidemia.