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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  P   v   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.

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