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Ranking and Characterization of Established BMI and Lipid Associated Loci as Candidates for Gene-Environment Interactions


Shungin, Dmitry; Deng, Wei Q.; Varga, Tibor V.; Luan, Jian'an; Mihailov, Evelin; Metspalu, Andres; GIANT Consortium,; Morris, Andrew P.; Forouhi, Nita G.; & Lindgren, Cecilia M., et al. (2017). Ranking and Characterization of Established BMI and Lipid Associated Loci as Candidates for Gene-Environment Interactions. PLOS Genetics, 13(6), e1006812. PMCID: PMC5489225


Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) 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), GxE 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 rho = 0.401 for triglycerides, and rho = 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 rho = 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 = 1.46x10-5), 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 GxE interaction P-values (Pint<0.05) were enriched with nominally significant Pv values (Pbinomial = 8.63x10-9 and 8.52x10-7 for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.


Reference Type

Journal Article

Year Published


Journal Title

PLOS Genetics


Shungin, Dmitry
Deng, Wei Q.
Varga, Tibor V.
Luan, Jian'an
Mihailov, Evelin
Metspalu, Andres
GIANT Consortium,
Morris, Andrew P.
Forouhi, Nita G.
Lindgren, Cecilia M.
Magnusson, Patrik K. E.
Pedersen, Nancy L.
Hallmans, Goran
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 J. F.
Chasman, Daniel I.
Ingelsson, Erik
Kilpelainen, Tuomas O.
Scott, Robert A.
Magi, Reedik
Pare, Guillaume
Franks, Paul W.