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.

The Role of Fat Mass and Obesity Associated Gene (Fto) in Satiety and Binge Eating Disorder

“…Although just one study found an association with obesity in this review, there are in previous studies a description of decreased response to satiety in children and adolescents when rs9939609 is present, confirmed in other studies [25][26][27][28] . As Cecil, Frayling et al also identified, rs9939609 carries an association with a higher Body Mass Index (BMI) in children and adults 29 .…”

Obesity and eating behaviour in children and adolescents: Contribution of common gene polymorphisms

“…Reports confi rm the role of FTO rs9939609, and surrogates for this variant, on BMI and fat mass in children and adolescents from Caucasian and non-Caucasian populations (Cecil et al, 2008;Fang et Xi et al, 2010). Additionally, several studies have confi rmed an increasing association between rs9939609 and BMI from early childhood to adolescence (Hardy et al, 2010;Haworth et al, 2008b;Rzehak et al, 2010;Sovio et al, 2011). Sovio and colleagues, in their meta-analysis of European children (8 cohorts, infants to 13 year olds) found that the minor (A) allele of the rs9939609 was additively associated with increasing BMI as early as 5.5 years onwards, and interestingly an inverse association was found below the age of 2.5 years (Sovio et al, 2011), supporting what is known about the timing of adiposity rebound and risk of adult obesity (Whitaker et al, 1998) and the interplay between behaviour (appetite, physical activity) and environment with age Wright et al, 2011).…”

“…Additionally, several studies have confi rmed an increasing association between rs9939609 and BMI from early childhood to adolescence (Hardy et al, 2010;Haworth et al, 2008b;Rzehak et al, 2010;Sovio et al, 2011). Sovio and colleagues, in their meta-analysis of European children (8 cohorts, infants to 13 year olds) found that the minor (A) allele of the rs9939609 was additively associated with increasing BMI as early as 5.5 years onwards, and interestingly an inverse association was found below the age of 2.5 years (Sovio et al, 2011), supporting what is known about the timing of adiposity rebound and risk of adult obesity (Whitaker et al, 1998) and the interplay between behaviour (appetite, physical activity) and environment with age Wright et al, 2011). A temporal dip in the effect of FTO rs9939609 on BMI in children is proposed at the mid-pubertal age of around 13-14 years which may be linked to alterations in physiologic and endocrine factors that trigger puberty (Rutters et al, 2011).…”

Associations of genetic variants for adult lipid levels with lipid levels in children. The Generation R Study

“…We weighted the SNPs in the GRS based on the effect estimates from the GWAS in adults. Effect sizes of individual SNPs may vary across the life course and adult weights may not appropriately cover the true effect sizes in children (27). There is a small GWAS available in children, but for proper estimation of the appropriate weights in children, there is a need for large meta-analyses of GWASs in children on lipid phenotypes (11).…”