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

PLoS Genet. 2017 Jun 14;13(6):e1006812. doi: 10.1371/journal.pgen.1006812. eCollection 2017 Jun.

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 (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm 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 Pv and Pm 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 Pv distribution (Pbinomial <0.05). SNPs from the top 1% of the Pm distribution for BMI had more significant Pv values (PMann-Whitney = 1.46×10-5), and the odds ratio of SNPs with nominally significant (<0.05) Pm and Pv was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (Pint<0.05) were enriched with nominally significant Pv values (Pbinomial = 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.

Publication types

  • Meta-Analysis

MeSH terms

  • Body Mass Index
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / genetics*
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Gene-Environment Interaction*
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Obesity / blood
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci / genetics
  • Risk Factors
  • Smoking / genetics

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL