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  • Sovio, U; Mook-Kanamori, DO; Warrington, NM; Lawrence, R; Briol- lais, L; Palmer, CN; Cecil, J; Sandling, JK; Syvnen, AC; Kaakinen, M; Beilin, LJ; Millwood, IY; Bennett, AJ; Laitinen, J; Pouta, A; Molitor, J; Davey Smith, G; Ben-Shlomo, Y; Jaddoe, VW; Palmer, LJ; Pennell, CE; Cole, TJ; McCarthy, MI; Jrvelin, MR; Timpson, NJ; Early Growth Genetics Consortium, (2011) Association between Common Variation at the FTO Locus and Changes in Body Mass In- dex from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development. PLoS genetics, 7 (2). e1001307. ISSN 1553-7390 DOI: https://doi.org/10.1371/journal.pgen.1001307

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  • Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development Ulla Sovio1,2., Dennis O. Mook-Kanamori3,4,5., Nicole M. Warrington6., Robert Lawrence7., Laurent

    Briollais8, Colin N. A. Palmer9, Joanne Cecil10¤, Johanna K. Sandling11, Ann-Christine Syvänen11, Marika

    Kaakinen12,13, Lawrie J. Beilin14, Iona Y. Millwood1,15, Amanda J. Bennett16, Jaana Laitinen17, Anneli

    Pouta18, John Molitor1, George Davey Smith19,20, Yoav Ben-Shlomo20, Vincent W. V. Jaddoe3,4,5, Lyle J.

    Palmer21, Craig E. Pennell6, Tim J. Cole22*, Mark I. McCarthy16,23,24, Marjo-Riitta Järvelin1,12,13,18,

    Nicholas J. Timpson19,20*, Early Growth Genetics Consortium

    1 Department of Epidemiology and Biostatistics, Imperial College, London, United Kingdom, 2 The London School of Hygiene and Tropical Medicine, London, United

    Kingdom, 3 Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands, 4 Department of Epidemiology, Erasmus Medical Center, Rotterdam, The

    Netherlands, 5 The Generation R Study, Erasmus Medical Center, Rotterdam, The Netherlands, 6 School of Women’s and Infants’ Health, The University of Western

    Australia, Perth, Australia, 7 Centre for Genetic Epidemiology and Biostatistics, The University of Western Australia, Perth, Australia, 8 Samuel Lunenfeld Research Institute,

    Mount Sinai Hospital, University of Toronto, Toronto, Canada, 9 Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee,

    United Kingdom, 10 Bute Medical School, University of St Andrews, St Andrews, United Kingdom, 11 Molecular Medicine, Department of Medical Sciences, Uppsala

    University, Uppsala, Sweden, 12 Institute of Health Sciences, University of Oulu, Oulu, Finland, 13 Biocenter Oulu, University of Oulu, Oulu, Finland, 14 School of Medicine

    and Pharmacology, The University of Western Australia, Perth, Australia, 15 Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, United

    Kingdom, 16 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom, 17 Finnish Institute of Occupational Health, Oulu,

    Finland, 18 Department of Lifecourse and Services, National Institute of Health and Welfare, Oulu, Finland, 19 MRC Centre for Causal Analyses in Translational

    Epidemiology, University of Bristol, Bristol, United Kingdom, 20 Department of Social Medicine, University of Bristol, Bristol, United Kingdom, 21 Ontario Institute for

    Cancer Research and Samuel Lunenfeld Research Institute, Toronto, Canada, 22 MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London,

    United Kingdom, 23 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, 24 Oxford NIHR Biomedical Research Centre, Churchill

    Hospital, Oxford, United Kingdom

    Abstract

    An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta- analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10220) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10223). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (20.40% (95% CI: 20.74, 20.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (24.72% (25.81, 23.63), p = 10217), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

    Citation: Sovio U, Mook-Kanamori DO, Warrington NM, Lawrence R, Briollais L, et al. (2011) Association between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late Childhood: The Complex Nature of Genetic Association through Growth and Development. PLoS Genet 7(2): e1001307. doi:10.1371/journal.pgen.1001307

    Editor: Greg Gibson, Georgia Institute of Technology, United States of America

    Received May 25, 2010; Accepted January 12, 2011; Published February 17, 2011

    Copyright: � 2011 Sovio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    PLoS Genetics | www.plosgenetics.org 1 February 2011 | Volume 7 | Issue 2 | e1001307

  • Funding: The contributing studies received financial support from the following sources: ALSPAC - The UK Medical Research Council, the Wellcome Trust and the University of Bristol provide core support for ALSPAC. BCG - Follow-up was funded by grants from the UK Department of Health, British Heart Foundation, Diabetes UK, and British Lung Foundation. CH - We gratefully acknowledge the financial support of the University of Bristol, Cancer Research UK, and the Medical Research Council for different elements of the cohort follow-up. GENR - The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw). UFS - The study was supported by the Swedish Research Council for Medicine. NFBC1966 - Work on the NFBC1966 was supported by the Academy of Finland (104781), Medical Research Council, UK (studentship grant G0500539), and the Wellcome Trust (Project Grant GR069224). RAINE - The authors gratefully acknowledge the NH&MRC for their long term support over the last 20 years and also the following Institutions for providing funding for Core Management of the Raine Study: The University of Western Australia (UWA), Raine Medical Research Foundation, UWA Faculty of Medicine, Dentistry, and Health Sciences, The Telethon Institute for Child Health Research and Women and Infants Research Foundation. RAINE is currently supported by the National Health and Medical Research Council of Australia (Grant ID 403981 and ID 003209) and the Canadian Institutes of Health Research (Grant ID MOP-82893). EBS - This study was funded by the Biotechnology and Biological Sciences Research Council project grant D13460. In addition to this, contributing authors received financial support from the following sources: US was funded by the MRC UK studentship grant G0500539 and is currently funded by MRC. TJC is funded by the Medical Research Council (grant no G07000961). GDS works within the MRC Centre for Causal Analyses in Translational Epidemiology which is capacity funded by grant G0600705. VWVJ receives funding from the Netherlands Organization for Health Research (ZonMw 90700303). M-RJ: Academy of Finland (project grants 104781, 120315 and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Finland, the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the Medical Research Council, UK (Salve/PrevMetSyn). NJT is funded by the MRC Centre for Causal Analyses in Translational Epidemiology grant number G0600705. Th