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

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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.


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

publication date

  • June 2017

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