PLoS Genetics (Jun 2017)

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

  • Dmitry Shungin,
  • Wei Q Deng,
  • Tibor V Varga,
  • Jian'an Luan,
  • Evelin Mihailov,
  • Andres Metspalu,
  • GIANT Consortium,
  • Andrew P Morris,
  • Nita G Forouhi,
  • Cecilia Lindgren,
  • Patrik K E Magnusson,
  • Nancy L Pedersen,
  • Göran Hallmans,
  • Audrey Y Chu,
  • Anne E Justice,
  • Mariaelisa Graff,
  • Thomas W Winkler,
  • Lynda M Rose,
  • Claudia Langenberg,
  • L Adrienne Cupples,
  • Paul M Ridker,
  • Nicholas J Wareham,
  • Ken K Ong,
  • Ruth J F Loos,
  • Daniel I Chasman,
  • Erik Ingelsson,
  • Tuomas O Kilpeläinen,
  • Robert A Scott,
  • Reedik Mägi,
  • Guillaume Paré,
  • Paul W Franks

DOI
https://doi.org/10.1371/journal.pgen.1006812
Journal volume & issue
Vol. 13, no. 6
p. e1006812

Abstract

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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 (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.