Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel lipid loci

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five ancestry groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (P < 5 x 10-8) and suggestive (P < 1×10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci including nine associated with LDL, seven for HDL, and two for TG. Four loci showed significant interaction effects. Two loci were significant only in trans-ancestry analyses. Several loci include genes with known or suggested roles in adipose (APLNR, FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (APLNR, BRI3, FILIP1, FOXP1, LINC00290, LMBRD2, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.
Keywords: genome-wide association; lipids; cholesterol; low-density lipoprotein cholesterol; high-density lipoprotein cholesterol; triglyceride; educational attainment; gene-environment interactions.