Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Additional Metadata
Persistent URL dx.doi.org/10.1371/journal.pgen.1005378, hdl.handle.net/1765/98787
Journal PL o S Genetics (Online)
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/201379 - COPD Pathology: Addressing Critical gaps, Early Treatment and Innovative Concepts (COPACETIC), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201668 - European Collaborative Project on Inflamation and Vascular Wall Remodelling in Atherosclerosis (ATHEROREMO), This work was funded by the European Commission 7th Framework Programme; grant id fp7/279143 - Identification of epigenetic markers underlying increased risk of T2D in South Asians (EPI-MIGRANT), This work was funded by the European Commission 7th Framework Programme; grant id fp7/305739 - Personalized diagnostics and treatment of high risk coronary artery disease patients. (RISKYCAD), This work was funded by the European Commission 7th Framework Programme; grant id fp7/313010 - BBMRI - Large Prospective Cohorts (BBMRI-LPC), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201413 - European Network for Genetic and Genomic Epidemiology (ENGAGE), This work was funded by the European Commission 7th Framework Programme; grant id fp7/277849 - European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing (EURHEALTHAGEING), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201550 - European Network for Genetic-Epidemiological Studies: building a method to dissect complex genetic traits, using essential hypertension as a disease model (HYPERGENES), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201865 - GENETIC FACTORS FOR OSTEOPOROSIS (GEFOS), This work was funded by the European Commission 7th Framework Programme; grant id fp7/305507 - Heart OMics in AGEing (HOMAGE), This work was funded by the European Commission 7th Framework Programme; grant id fp7/278249 - Markers for Sub-Clinical Cardiovascular Risk Assessemnt (EU-MASCARA)
Citation
Winkler, T.W, Justice, A.E, Graff, M.J, Barata, L. (Llilda), Feitosa, M.F, Chu, S. (Su), … Loos, R.J.F. (2015). The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PL o S Genetics (Online), 11(10). doi:10.1371/journal.pgen.1005378