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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.

Sovio U, Mook-Kanamori DO, Warrington NM, Lawrence R, Briollais L, Palmer CN, Cecil J, Sandling JK, Syvänen AC, Kaakinen M, Beilin LJ, Millwood IY, Bennett AJ, Laitinen J, Pouta A, Molitor J, Davey Smith G, Ben-Shlomo Y, Jaddoe VW, Palmer LJ, Pennell CE, Cole TJ, McCarthy MI, Järvelin MR, Timpson NJ, Early Growth Genetics Consorti - PLoS Genet. (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Biostatistics, Imperial College, London, United Kingdom.

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.

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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).
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pgen-1001307-g001: 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).

Mentions: In meta-analyses above the age of 5.5 years (childhood) the minor allele (A) was associated additively with a higher BMI, though this was not detectable in the age stratum 11 to 13 years where the sample was small and where age associated increase in variance compromises analytical power. Expressed as a percentage change, the additive effect of each minor allele (A) was 0.7% (95% CI: 0.3, 1.1), 1.0% (95% CI: 0.6, 1.3), and 1.3% (95% CI: 0.6, 2.0) at 5.5–7, 7–9 and 9–11 years respectively. Maximum heterogeneity was high with I2 = 69.6% (95% CI: 22, 88). In contrast to this, each minor allele was associated with a lower BMI before the age of 2.5 years. The additive effect of each minor allele was −0.4% (95% CI: −0.6, −0.1), −0.3% (95% C%I: −0.6, −0.1) and −0.3% (95% CI: −0.5, 0.0) at age 0–0.5, 0.5–1.5 and 1.5–2.5 years respectively. Between 2.5 and 5.5 years there was no association between rs9939609 genotype and BMI. For these periods, maximum heterogeneity was high with I2 = 44.1% (95% CI: 0, 81). Figure 1 shows meta-analysis results representing major observations throughout the age range. Similar results (not shown) were found for weight/heightp.


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.

Sovio U, Mook-Kanamori DO, Warrington NM, Lawrence R, Briollais L, Palmer CN, Cecil J, Sandling JK, Syvänen AC, Kaakinen M, Beilin LJ, Millwood IY, Bennett AJ, Laitinen J, Pouta A, Molitor J, Davey Smith G, Ben-Shlomo Y, Jaddoe VW, Palmer LJ, Pennell CE, Cole TJ, McCarthy MI, Järvelin MR, Timpson NJ, Early Growth Genetics Consorti - PLoS Genet. (2011)

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).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040655&req=5

pgen-1001307-g001: 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).
Mentions: In meta-analyses above the age of 5.5 years (childhood) the minor allele (A) was associated additively with a higher BMI, though this was not detectable in the age stratum 11 to 13 years where the sample was small and where age associated increase in variance compromises analytical power. Expressed as a percentage change, the additive effect of each minor allele (A) was 0.7% (95% CI: 0.3, 1.1), 1.0% (95% CI: 0.6, 1.3), and 1.3% (95% CI: 0.6, 2.0) at 5.5–7, 7–9 and 9–11 years respectively. Maximum heterogeneity was high with I2 = 69.6% (95% CI: 22, 88). In contrast to this, each minor allele was associated with a lower BMI before the age of 2.5 years. The additive effect of each minor allele was −0.4% (95% CI: −0.6, −0.1), −0.3% (95% C%I: −0.6, −0.1) and −0.3% (95% CI: −0.5, 0.0) at age 0–0.5, 0.5–1.5 and 1.5–2.5 years respectively. Between 2.5 and 5.5 years there was no association between rs9939609 genotype and BMI. For these periods, maximum heterogeneity was high with I2 = 44.1% (95% CI: 0, 81). Figure 1 shows meta-analysis results representing major observations throughout the age range. Similar results (not shown) were found for weight/heightp.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology and Biostatistics, Imperial College, London, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus