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Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions
Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ, Dept Odontol, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Unit Med, Umea, Sweden.;MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
Univ Toronto, Dept Stat Sci, Toronto, ON, Canada..
Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Univ Copenhagen, Fac Hlth & Med Sci, Translat Dis Syst Biol Grp, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark.;Lund Univ, Exercise Physiol Grp, Dept Hlth Sci, Lund, Sweden..
Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006812Article in journal (Refereed) Published
Abstract [en]

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 (P-v), GxE 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 rho = 0.401 for triglycerides, and rho = 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 rho = 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 (Pmann-Whitney = 1.46x10(-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 GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 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.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2017. Vol. 13, no 6, article id e1006812
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-330756DOI: 10.1371/journal.pgen.1006812ISI: 000404512600010PubMedID: 28614350OAI: oai:DiVA.org:uu-330756DiVA, id: diva2:1146635
Funder
Swedish Research CouncilSwedish Heart Lung FoundationNovo Nordisk
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-03Bibliographically approved

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