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

Title: 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
Authors: Sovio, U
Mook-Kanamori, DO
Warrington, NM
Lawrence, R
Briollais, L
Palmer, CNA
Cecil, J
Sandling, JK
Syvanen, A-C
Kaakinen, M
Beilin, LJ
Millwood, IY
Bennett, AJ
Laitinen, J
Pouta, A
Molitor, J
Smith, GD
Ben-Shlomo, Y
Jaddoe, VWV
Palmer, LJ
Pennell, CE
Cole, TJ
McCarthy, MI
Jarvelin, M-R
Timpson, NJ
Item Type: Journal Article
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.
Issue Date: 17-Feb-2011
Date of Acceptance: 12-Jan-2011
ISSN: 1553-7390
Publisher: Public Library of Science
Journal / Book Title: PLOS Genetics
Volume: 7
Issue: 2
Copyright Statement: © 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.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: G0801056B
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Body Height
Body Mass Index
Body Weight
Child, Preschool
Cross-Sectional Studies
Genetic Association Studies
Genetic Loci
Genetic Variation
Growth and Development
Infant, Newborn
Longitudinal Studies
Meta-Analysis as Topic
Polymorphism, Single Nucleotide
Early Growth Genetics Consortium
Developmental Biology
0604 Genetics
Publication Status: Published
Article Number: ARTN e1001307
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care

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