Evidence for Age As a Modifier of Genetic Associations for Lipid Levels

In order to identify novel genetic variants that influence plasma lipid concentrations, we performed a genome-wide association study (GWAS) comprised of 411 children under 18 years of age, ascertained at St. Jude Children's Research Hospital, all of whom were of European, African, or Mexican descent. Promising associations (p < 10(-5)) were subsequently examined in 1040 additional youths and 3508 adults from the Third National Health and Nutrition Examination Survey (NHANES III), a diverse population-based study. Three genotype-phenotype associations replicated in NHANES III youths and three associated in NHANES III adults at p < 0.05; however, no single association was significant in both youths and adults. The most significant association (p = 0.009) in NHANES III youths was between low-density lipoprotein cholesterol (LDL-C) and intronic rs2429917 among participants of African descent. Given the known age dependency of lipid levels, we also tested for gene-age interactions in NHANES III participants across all ages. We identified a significant (p = 0.024) age-dependent association between SGSM2 rs2429917 and LDL-C. This finding illustrates the utility of using children to discover novel variants associated with complex phenotypes and the importance of considering age-dependent genetic effects in association studies of lipid levels.