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

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, 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 providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shap
Funding:Funding for this study was provided by the Aarne Koskelo Foundation; the Aase and Ejner Danielsens Foundation; the Academy of Finland (40758, 41071, 77299, 102318, 104781, 117787, 117844, 118590, 120315, 121584, 123885, 124243, 124282, 126925, 129269, 129293, 129378, 130326, 134309, 134791, 136895, 139635, 211497, 263836, 263924, 1114194, 24300796); the Agency for Health Care Policy Research (HS06516); the Agency for Science, Technology and Research of Singapore (A*STAR); the Ahokas Foundation; the ALF/LUA research grant in Gothenburg; the ALK-Abello A/S (Horsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories Denmark; the Althingi (the Icelandic Parliament); the American Heart Association (AHA; 13POST16500011); the ANR ("Agence Nationale de la 359 Recherche"); the Ark (NHMRC Enabling Facility); the Arthritis Research UK (19542, 18030); the AstraZeneca; the Augustinus Foundation; the Australian National Health and Medical Research Council (NHMRC; 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506); the Australian Research Council (ARC; DP0770096 and DP1093502); the Becket Foundation; the bi-national BMBF/ANR funded project CARDomics (01KU0908A); the Biobanking and Biomolecular Resources Research Infrastructure (BBMRINL; 184.021.007, CP 32); the Biocentrum Helsinki; the Boehringer Ingelheim Foundation; the British Heart Foundation (RG/10/12/28456, SP/04/ 002); the Canadian Institutes for Health Reseaerch (FRCN-CCT-83028); the Cancer Research UK (C490/A10124, C490/A10119); the Center for Medical Systems Biology (CMSB; NWO Genomics); the Centers for Disease Control and Prevention and Association of Schools of Public Health (1734, S043, S3486); the Centre of Excellence Baden-Wurttemberg Metabolic Disorders; the Chief Scientist Office of the Scottish Government; the Clinical Research Facility at Guys & St Thomas NHS Foundation Trust; the Contrat de Projets Etat-Region (