This study identifies 95 genetic loci associated with serum lipid concentrations in over 100,000 individuals of European ancestry, with 59 of these loci showing genome-wide significant association for the first time. These loci contribute to normal variation in lipid traits and extreme lipid phenotypes, and are also associated with coronary artery disease (CAD). The study evaluates the relevance of these loci in non-European populations and assesses their clinical and biological significance. It finds that the identified loci are relevant in East Asians, South Asians, and African Americans, and that some of these loci are associated with CAD. Functional studies in mouse models validate three novel genes—*GALNT2*, *PPP1R3B*, and *TTC39B*—as regulators of lipid metabolism. The findings provide a foundation for understanding lipoprotein metabolism and identifying new therapeutic opportunities for preventing CAD.This study identifies 95 genetic loci associated with serum lipid concentrations in over 100,000 individuals of European ancestry, with 59 of these loci showing genome-wide significant association for the first time. These loci contribute to normal variation in lipid traits and extreme lipid phenotypes, and are also associated with coronary artery disease (CAD). The study evaluates the relevance of these loci in non-European populations and assesses their clinical and biological significance. It finds that the identified loci are relevant in East Asians, South Asians, and African Americans, and that some of these loci are associated with CAD. Functional studies in mouse models validate three novel genes—*GALNT2*, *PPP1R3B*, and *TTC39B*—as regulators of lipid metabolism. The findings provide a foundation for understanding lipoprotein metabolism and identifying new therapeutic opportunities for preventing CAD.