Blog
About

64
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      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

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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 = 10 −20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10 −23). 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 (−0.40% (95% CI: −0.74, −0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (−4.72% (−5.81, −3.63), p = 10 −17), 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.

          Author Summary

          Variation at the FTO locus is reliably associated with BMI and adiposity-related traits, but little is still known about the effects of variation at this gene, particularly in children. We have examined a large collection of samples for which both genotypes at rs9939609 and multiple measurements of BMI are available. We observe a positive association between the minor allele (A) at rs9939609 and BMI emerging in childhood that has the characteristics of a shift in the age scale leading simultaneously to lower BMI during infancy and higher BMI in childhood. Assessed in cross section and longitudinally, we find evidence of variation at rs9939609 being associated with the timing of AR and the concert of events expected with such a change to the BMI curve. Importantly, the apparently negative association between the minor allele (A) and BMI in early life, which is then followed by an earlier AR and greater BMI in childhood, is a pattern known to be associated with both the risk of adult BMI and metabolic disorders such as type 2 diabetes (T2D). These findings are important in our understanding of the contribution of FTO to adiposity, but also in light of efforts to appreciate genetic effects in a lifecourse context.

          Related collections

          Most cited references 43

          • Record: found
          • Abstract: found
          • Article: not found

          Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

          Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.

            Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Early life risk factors for obesity in childhood: cohort study.

              To identify risk factors in early life (up to 3 years of age) for obesity in children in the United Kingdom. Prospective cohort study. Avon longitudinal study of parents and children, United Kingdom. 8234 children in cohort aged 7 years and a subsample of 909 children (children in focus) with data on additional early growth related risk factors for obesity. Obesity at age 7 years, defined as a body mass index (3) 95th centile relative to reference data for the UK population in 1990. Eight of 25 putative risk factors were associated with a risk of obesity in the final models: parental obesity (both parents: adjusted odds ratio, 10.44, 95% confidence interval 5.11 to 21.32), very early (by 43 months) body mass index or adiposity rebound (15.00, 5.32 to 42.30), more than eight hours spent watching television per week at age 3 years (1.55, 1.13 to 2.12), catch-up growth (2.60, 1.09 to 6.16), standard deviation score for weight at age 8 months (3.13, 1.43 to 6.85) and 18 months (2.65, 1.25 to 5.59); weight gain in first year (1.06, 1.02 to 1.10 per 100 g increase); birth weight, per 100 g (1.05, 1.03 to 1.07); and short (< 10.5 hours) sleep duration at age 3 years (1.45, 1.10 to 1.89). Eight factors in early life are associated with an increased risk of obesity in childhood.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                February 2011
                February 2011
                17 February 2011
                : 7
                : 2
                Affiliations
                [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
                Georgia Institute of Technology, United States of America
                Author notes

                ¤: Current address: School of Medicine, University of St. Andrews, St. Andrews, United Kingdom

                Conceived and designed the experiments: US DOMK NMW LB GDS TJC MIM NJT. Analyzed the data: US DOMK NMW RL LJB TJC NJT. Contributed reagents/materials/analysis tools: CNAP JC JKS ACS MK IYM AJB JL AP JM GDS YBS VWVJ LJP CEP MRJ NJT. Wrote the paper: DOMK NJT. Involved in the writing stages of this work: VWVJ.

                Article
                10-PLGE-RA-NV-3282R3
                10.1371/journal.pgen.1001307
                3040655
                21379325
                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.
                Page count
                Pages: 13
                Categories
                Research Article
                Genetics and Genomics/Complex Traits

                Genetics

                Comments

                Comment on this article