TY - JOUR
T1 - Association between common variation at the FTO locus and changes in Body Mass Index from infancy to late childhood
T2 - the complex nature of genetic association through growth and development
AU - Early Growth Genetics Consortium
AU - Sovio, Ulla
AU - Mook-Kanamori, Dennis O.
AU - Warrington, Nicole M.
AU - Lawrence, Robert
AU - Briollais, Laurent
AU - Palmer, Colin N.A.
AU - Cecil, Joanne Elizabeth
AU - Sandling, Johanna
AU - Syvänen, Ann-Christine
AU - Kaakinen, Marika
AU - Beilin, Lawrie
AU - Millwood, Iona
AU - Bennett, Amanda
AU - Laitinen, Jaana
AU - Pouta, Anneli
AU - Molitor, John
AU - Davey Smith, George
AU - Ben-Shlomo, Yoav
AU - Jaddoe, Vincent
AU - Palmer, Lyle
AU - Pennell, Craig
AU - Cole, Tim
AU - McCarthy, Mark
AU - Järvelin, Marjo-Riitta
AU - Timpson, Nicholas
PY - 2011
Y1 - 2011
N2 - An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We metaanalyzed 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 = 10220) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10223). 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 (20.40% (95% CI: 20.74, 20.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (24.72% (25.81, 23.63), p = 10217), 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.
AB - An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We metaanalyzed 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 = 10220) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10223). 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 (20.40% (95% CI: 20.74, 20.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (24.72% (25.81, 23.63), p = 10217), 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.
U2 - 10.1371/journal.pgen.1001307
DO - 10.1371/journal.pgen.1001307
M3 - Article
SN - 1553-7390
VL - 7
JO - PLoS Genetics
JF - PLoS Genetics
IS - 2
M1 - e1001307
ER -