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

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  • Shungin, Dmitry
    • Other Affiliation: Department of Clinical Sciences; Genetic & Molecular Epidemiology Unit; Lund University Diabetes Centre; Skåne University Hospital
  • Deng, Wei Q.
    • Other Affiliation: Department of Statistical Sciences; University of Toronto
  • Varga, Tibor V.
    • Other Affiliation: Novo Nordisk Foundation Center for Protein Research; Translational Disease Systems Biology Group; Faculty of Health and Medical Sciences; University of Copenhagen
  • Luan, Jian'an
    • Other Affiliation: MRC Epidemiology Unit; University of Cambridge; Institute of Metabolic Science; Addenbrooke’s Hospital
  • Mihailov, Evelin
    • Other Affiliation: Estonian Genome Center; University of Tartu
  • Metspalu, Andres
    • Other Affiliation: Institute of Molecular and Cell Biology; University of Tartu
  • Morris, Andrew P.
    • Other Affiliation: Wellcome Trust Centre for Human Genetics; University of Oxford
  • Forouhi, Nita G.
    • Other Affiliation: MRC Epidemiology Unit; University of Cambridge; Institute of Metabolic Science; Addenbrooke’s Hospital
  • Lindgren, Cecilia
    • Other Affiliation: Wellcome Trust Centre for Human Genetics; University of Oxford
  • Magnusson, Patrik K. E.
    • Other Affiliation: Department of Medical Epidemiology and Biostatistics; Karolinska Institutet
  • Pedersen, Nancy L.
    • Other Affiliation: Department of Medical Epidemiology and Biostatistics; Karolinska Institutet
  • Hallmans, Göran
    • Other Affiliation: Department of Biobank Research; Umeå University
  • Chu, Audrey Y.
    • Other Affiliation: Harvard Medical School; Boston
  • Justice, Anne E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Graff, Mariaelisa
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Winkler, Thomas W.
    • ORCID: 0000-0003-0292-5421
    • Other Affiliation: Department of Genetic Epidemiology; University of Regensburg
  • Rose, Lynda M.
    • Other Affiliation: Division of Preventive Medicine; Brigham and Women's Hospital
  • Langenberg, Claudia
    • Other Affiliation: MRC Epidemiology Unit; University of Cambridge; Institute of Metabolic Science; Addenbrooke’s Hospital
  • Cupples, L. Adrienne
    • Other Affiliation: The NHLBI Framingham Heart Study
  • Ridker, Paul M.
    • Other Affiliation: Division of Preventive Medicine; Brigham and Women's Hospital
  • Wareham, Nicholas J.
    • ORCID: 0000-0003-1422-2993
    • Other Affiliation: MRC Epidemiology Unit; University of Cambridge; Institute of Metabolic Science; Addenbrooke’s Hospital
  • Ong, Ken K.
    • Other Affiliation: MRC Epidemiology Unit; University of Cambridge; Institute of Metabolic Science; Addenbrooke’s Hospital
  • Loos, Ruth J. F.
    • Other Affiliation: The Genetics of Obesity and Related Metabolic Traits Program; Icahn School of Medicine at Mount Sinai
  • Chasman, Daniel I.
    • Other Affiliation: Division of Preventive Medicine; Brigham and Women's Hospital
  • Ingelsson, Erik
    • Other Affiliation: Science for Life Laboratory; Uppsala University
  • Kilpeläinen, Tuomas O.
    • Other Affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research; Section of Metabolic Genetics; Faculty of Health and Medical Sciences; University of Copenhagen
  • Scott, Robert A.
    • Other Affiliation: MRC Epidemiology Unit; University of Cambridge; Institute of Metabolic Science; Addenbrooke’s Hospital
  • Mägi, Reedik
    • Other Affiliation: Wellcome Trust Centre for Human Genetics; University of Oxford
  • Paré, Guillaume
    • ORCID: 0000-0002-6795-4760
    • Other Affiliation: Department of Pathology and Molecular Medicine; McMaster University
  • Franks, Paul W.
    • Other Affiliation: Oxford Centre for Diabetes; Endocrinology & Metabolism; Radcliff Department of Medicine; University of Oxford
Abstract
  • 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.
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 13
Journal issue
  • 6
Page start
  • e1006812
Language
  • English
ISSN
  • 1553-7390
  • 1553-7404

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