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

Author:
  • Dmitry Shungin
  • Wei Q. Deng
  • Tibor V. Varga
  • Jian'an Luan
  • Evelin Mihailov
  • Andres Metspalu
  • 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
  • Adrienne L. 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
Publishing year: 2017
Language: English
Publication/Series: PLoS Genetics
Volume: 13
Issue: 6
Document type: Journal article
Publisher: Public Library of Science

Abstract english

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 Pvand Pmwere 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 Pvand Pmwere 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 Pvdistribution (Pbinomial<0.05). SNPs from the top 1% of the Pmdistribution for BMI had more significant Pvvalues (PMann–Whitney= 1.46×10−5), and the odds ratio of SNPs with nominally significant (<0.05) Pmand Pvwas 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 Pvvalues (Pbinomial= 8.63×10−9and 8.52×10−7for 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.

Keywords

  • Medical Genetics

Other

Published
  • Genetic and Molecular Epidemiology
  • ISSN: 1553-7390
Paul Franks
E-mail: paul.franks [at] med.lu.se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49

60-12-021

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Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00