Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions

Abstract

Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P$_v$), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (P$_m$). Correlations between P$_v$ and P$_m$ were stronger for SNPs with established marginal effects (Spearman's ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When P$_v$ and P$_m$ were compared for all pruned SNPs, only BMI was statistically significant (Spearman's ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P$v$ distribution (P${binomial}$ <0.05). SNPs from the top 1% of the P$m$ distribution for BMI had more significant Pv values (P${Mann-Whitney}$ = 1.46×10$^{-5}$), and the odds ratio of SNPs with nominally significant (<0.05) P$_m$ and P$v$ was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (P${int}$<0.05) were enriched with nominally significant P$v$ values (P${binomial}$ = 8.63×10$^{-9}$ and 8.52×10$^{-7}$ for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them.