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

• DOI: 10.1371/journal.pgen.1001307
• Publication Date: 2011-02-17T19:43:42Z
• Authors: Ulla Sovio; Dennis O. Mook-Ka...; Nicole M. Warrington; Robert Lawrence; Laurent Briollais; Colin N. A. Palmer; Joanne Cecil; Johanna K. Sandling; Ann-Christine Syv...; Marika Kaakinen; Lawrie J. Beilin; Iona Y. Millwood; Amanda J. Bennett; Jaana Laitinen; Anneli Pouta; John Molitor; George Davey Smith; Yoav Ben-Shlomo; Vincent W. V. Jaddoe; Lyle J. Palmer; Craig E. Pennell; Tim J. Cole; Mark I. McCarthy; Marjo-Riitta Järv...; Nicholas J. Timpson
• Keywords: Male; EMC MM-04-54-08-A; 0301 basic medicine; FOOD-INTAKE; CHILDREN; QH426-470; 796; Body Mass Index; ADULT OBESITY; 1306 Cancer Research; Longitudinal Studies; GENETICS & HEREDITY; Child; Adiposity; Genetics & Heredity; 2. Zero hunger; BIRTH COHORT; Single Nucleotide; FAT MASS; Child, Preschool; ADIPOSITY; Female; Growth and Development; Life Sciences & Biomedicine; Research Article; 2716 Genetics (clinical); EMC NIHES-01-64-02; Adolescent; Genotype; 610; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; 1105 Dentistry; QH426 Genetics; Polymorphism, Single Nucleotide; 03 medical and health sciences; AGE; 1311 Genetics; Meta-Analysis as Topic; 1312 Molecular Biology; Genetics; Humans; Polymorphism; Preschool; QH426; Alleles; Genetic Association Studies; 0604 Genetics; Science & Technology; Early Growth Genetics Consortium; Body Weight; Infant, Newborn; Proteins; Genetic Variation; Infant; Newborn; Body Height; ENERGY-INTAKE; Cross-Sectional Studies; Genetic Loci; RISK-FACTORS; WEIGHT; Developmental Biology

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.