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

Research output: Contribution to journalArticle


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.


  • 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
  • GIANT Consortium
External organisations
  • Umeå University
  • Broad Institute
  • Skåne University Hospital
  • Harvard University
  • University of Toronto
  • University of Copenhagen
  • Novo Nordisk Foundation Center for Protein Research
  • University of Cambridge
  • University of Tartu
  • Wellcome Trust Centre for Human Genetics
  • University of Liverpool
  • Karolinska Institutet
  • Harvard Medical School
  • University of North Carolina
  • University of Regensburg
  • Brigham and Women's Hospital / Harvard Medical School
  • University College London
  • Boston University
  • Framingham Heart Study
  • Icahn School of Medicine at Mount Sinai
  • Uppsala University
  • Stanford University
  • University of Oxford
  • McMaster University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Article numbere1006812
JournalPLoS Genetics
Issue number6
Publication statusPublished - 2017
Publication categoryResearch