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

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.

Figure 1. Results of the meta-analyses of the association between each additional minor allele (A) at rs9939609 and BMI by age (1a–1j).

Figures are shown in units of lnBMI—to convert to percentages multiply by 100. Maximum heterogeneity in meta-analyses was I² 81.7% (95% CI: 53, 93).

Figure 2. Curves of median BMI by age and genotype at rs9939609, estimated by the LMS method and adjusted for study and sex.

Figure 3. Curves of median weight (above) and height (below) by age and genotype at rs9939609, estimated by the LMS method and adjusted for study and sex.

Figure 4. Estimation of the optimal age scaling effect per minor A allele for BMI.

Minimum deviance corresponds to a scale factor of 2.4% (above), and adjusting for this factor synchronises the ages at adiposity rebound by genotype (below).