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

Abstract

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: 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 population 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 × 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). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, 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. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Keywords: cholesterol; educational attainment; genome-wide association study; lipids; meta-analysis; triglycerides.

FIGURE 1

Overview. A two-stage meta-analysis of gene-educational attainment interactions on lipid traits considering two educational attainment (a surrogate for socioeconomic status) was performed. Subsequently, a meta-analysis combining results of Stages 1 and 2 was performed to identify known and novel loci for lipid traits. Identified loci include genes with known or suggested roles in brain, adipose, and liver biology. Functional annotation, expression quantitative trait loci (eQTLs), and potential druggability of targets was explored. In the Manhattan plot, known and novel loci are depicted in gray and red/blue, respectively. GxE, gene-environment interaction; GradCol, graduated college; SES, socioeconomic status; SomeCol, some college.

FIGURE 2

Interaction effects of Locus 15 (rs35287906; STIM1) identified through combined Stage 1 and Stage 2 interaction effects with GradCol for LDL in EUR and CPA. Forest plots show β values (95% confidence intervals) and p-values (1 DF) for the rs35287906 × GradCol interaction term in linear regression models of LDL adjusted for age, sex, field center (for multi-center studies), and principal components. Results shown are for each EUR study, as well as the population-specific combined Stage 1 and 2 meta-analysis results. The interaction effect β_G Educ corresponds to the difference in genetic effects between higher (β_G1 = −5.25 mg/dL per minor allele) and lower education (β_G0 = 3.41 mg/dL per minor allele), for a combined interaction effect of −8.66 mg/dL. AF, coded allele frequency; N, sample size.