The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Thomas W. Winkler*, Anne E. Justice, Mariaelisa Graff, Llilda Barata, Mary F. Feitosa, Su Chu, Jacek Czajkowski, Tonu Esko, Tove Fall, Tuomas O. Kilpelainen, Yingchang Lu, Reedik Magi, Evelin Mihailov, Tune H. Pers, Sina Rueeger, Alexander Teumer, Georg B. Ehret, Teresa Ferreira, Nancy L. Heard-Costa, Juha KarjalainenVasiliki Lagou, Anubha Mahajan, Michael D. Neinast, Inga Prokopenko, Jeannette Simino, Tanya M. Teslovich, Rick Jansen, Harm-Jan Westra, Charles C. White, Irene Mateo Leach, Ilja M. Nolte, Serena Sanna, Jana V. van Vliet-Ostaptchouk, Niek Verweij, Stephan J. L. Bakker, Marcel Bruinenberg, Catharina A. Hartman, Hans Hillege, Meena Kumari, Ronald P. Stolk, Morris A. Swertz, Peter J. van der Most, Judith M. Vonk, Folkert W. Asselbergs, Lude Franke, Ron T. Gansevoort, Pim van der Harst, Albertine J. Oldehinkel, Brenda W. Penninx, Harold Snieder, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global BPGen Consortium, ICBP Consortium, MAGIC Consortium

*Corresponding author for this work

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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 similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 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 providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

Original languageEnglish
Article numbere1005378
Number of pages42
JournalPLoS genetics
Issue number10
Publication statusPublished - Oct-2015


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