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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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Curves of median BMI by age and genotype at rs9939609, estimated by the LMS method and adjusted for study and sex.
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pgen-1001307-g002: Curves of median BMI by age and genotype at rs9939609, estimated by the LMS method and adjusted for study and sex.

Mentions: To clarify the age trends in BMI for each genotype, median curves were estimated using the LMS method to adjust for age-specific heteroscedasticity and skewness. Figure 2 shows the median curves by genotype, where comparison shows three distinct features: (i) BMI is higher for A carriers later in childhood, but lower early in childhood; (ii) AR is earlier for A carriers; (iii) the A allele effects are additive in that the TA group is consistently midway between AA and TT. Curves for weight and height (Figure 3) show genotype differences for weight that emerge only after age 4, and height differences that are small at all ages. The differences in age at AR (Figure 2) can be removed by estimating a developmental age scaling effect per A allele of 2.79% (95% CI: 2.35, 3.23), such that the age scale in the AA group is shrunk, and in the TT group stretched, by 2.79% relative to TA. However there remains a rising BMI trend in AA relative to TT which is confirmed by fitting a log age by genotype interaction (coefficient 0.039 kg/m2 (0.031, 0.046) per log age unit per A allele, p = 10−23). Fitting the interaction reduces the optimal age scaling slightly to 2.37% (95% CI: 1.87, 2.87, p = 10−20), but provides evidence suggesting that the two processes together, developmental differences on the age scale and on the BMI scale, explain the complex age-related genotype effects on BMI in childhood. Figure 4 shows the estimation of this optimal scaling (top) and the curves of Figure 2 scaled by this amount (bottom), where now AR occurs at the same developmental ‘age’ for all groups. For comparison the optimal age scale to adjust for genotype differences in height (Figure 3) is 0.3% (0.2, 0.4), a value attaining statistical confidence, but far smaller than for BMI. Thus FTO appears to affect BMI developmental age much more than it does height developmental age.


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)

Curves of median BMI by age and genotype at rs9939609, estimated by the LMS method and adjusted for study and sex.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1001307-g002: Curves of median BMI by age and genotype at rs9939609, estimated by the LMS method and adjusted for study and sex.
Mentions: To clarify the age trends in BMI for each genotype, median curves were estimated using the LMS method to adjust for age-specific heteroscedasticity and skewness. Figure 2 shows the median curves by genotype, where comparison shows three distinct features: (i) BMI is higher for A carriers later in childhood, but lower early in childhood; (ii) AR is earlier for A carriers; (iii) the A allele effects are additive in that the TA group is consistently midway between AA and TT. Curves for weight and height (Figure 3) show genotype differences for weight that emerge only after age 4, and height differences that are small at all ages. The differences in age at AR (Figure 2) can be removed by estimating a developmental age scaling effect per A allele of 2.79% (95% CI: 2.35, 3.23), such that the age scale in the AA group is shrunk, and in the TT group stretched, by 2.79% relative to TA. However there remains a rising BMI trend in AA relative to TT which is confirmed by fitting a log age by genotype interaction (coefficient 0.039 kg/m2 (0.031, 0.046) per log age unit per A allele, p = 10−23). Fitting the interaction reduces the optimal age scaling slightly to 2.37% (95% CI: 1.87, 2.87, p = 10−20), but provides evidence suggesting that the two processes together, developmental differences on the age scale and on the BMI scale, explain the complex age-related genotype effects on BMI in childhood. Figure 4 shows the estimation of this optimal scaling (top) and the curves of Figure 2 scaled by this amount (bottom), where now AR occurs at the same developmental ‘age’ for all groups. For comparison the optimal age scale to adjust for genotype differences in height (Figure 3) is 0.3% (0.2, 0.4), a value attaining statistical confidence, but far smaller than for BMI. Thus FTO appears to affect BMI developmental age much more than it does height developmental age.

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