Background-Genome-wide association studies (GWAS) have identified a number of single-nucleotide polymorphisms (SNPs) associated with serum lipid level in populations of European descent. The individual and the cumulative effect of these SNPs on blood lipids are largely unclear for the US population. Methods and Results-Using data from the second phase (1991)(1992)(1993)(1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative survey of the US population, we examined associations of 57 GWAS-identified or well-established lipid-related genetic loci with plasma concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, triglycerides, total cholesterol/ HDL-C ratio, and non-HDL-C. We used multivariable linear regression to examine single SNP associations and the cumulative effect of multiple SNPs (using a genetic risk score [GRS]) on blood lipid levels. Analyses were conducted in adults from each of the 3 major racial/ethnic groups in the United States: non-Hispanic whites (nϭ2296), non-Hispanic blacks (nϭ1699), and Mexican Americans (nϭ1713). Allele frequencies for all SNPs varied significantly by race/ethnicity, except rs3764261 in CETP. Individual SNPs had very small effects on lipid levels, effects that were generally consistent in direction across racial/ethnic groups. More GWAS-validated SNPs were replicated in non-Hispanic whites (Ͻ67%) than in non-Hispanic blacks (Ͻ44%) or Mexican Americans (Ͻ44%). GRSs were strongly associated with increased lipid levels in each racial/ethnic group. The combination of all SNPs into a weighted GRS explained no more than 11% of the total variance in blood lipid levels. Conclusions-Our findings show that the combined association of SNPs, based on a GRS, was strongly associated with increased blood lipid measures in all major race/ethnic groups in the United States, which may help in identifying subgroups with a high risk for an unfavorable lipid profile. (Circ Cardiovasc Genet. 2011;4:523-533.)Key Words: nutrition surveys Ⅲ lipids Ⅲ continental population groups Ⅲ ethnology Ⅲ cholesterol Ⅲ genetics Ⅲ risk G enome-wide association studies (GWAS) have successfully identified numerous genetic loci associated with blood lipid levels, which are known risk factors for cardiovascular disease. [1][2][3][4][5][6][7][8] These studies have confirmed some risk loci identified in previous candidate gene and linkage analyses, and they have uncovered a panel of new candidate loci for lipid traits such as total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Meta-analyses of GWAS have proven fruitful as well. A recent meta-analysis of blood lipid studies reported significant associations of 95 loci with lipid traits in Ͼ100 000 individuals of European ancestry, most of which had concordant effects in nonEuropean populations. 3 Nevertheless, studies have reported racial/ethnic variation in blood li...