From modeling to measurement: developmental trends in genetic influence on adiposity in childhood

Abstract

Objective: Evidence of increasing heritability of BMI over childhood can seem paradoxical given longer exposure to environmental influences. Genomic data were used to provide direct evidence of developmental increases in genetic influence.

Methods: BMI standard deviation scores (BMI-SDS) at ages 4 and 10 were calculated for 2,556 twin pairs in the Twins Early Development Study. Twin analyses estimated heritability of BMI-SDS at each age and the longitudinal genetic correlation. One randomly selected twin per pair was genotyped. Genome-wide complex trait analysis (GCTA) determined DNA-based heritability at each age and the longitudinal genomic correlation. Associations with a polygenic obesity risk score (PRS) using 28 obesity-related single nucleotide polymorphisms (SNPs) were assessed at each age, with bootstrapping to test the significance of the increase in variance explained.

Results: Twin-estimated heritability increased from age 4 (0.43; 95% CI: 0.35-0.53) to 10 (0.82; 0.74-0.88). GCTA-estimated heritability went from non-significant at 4 (0.20; -0.21 to 0.61) to significant at 10 (0.29; 0.01-0.57). Longitudinal genetic correlations derived from twins (0.58) and GCTA (0.66) were similar. The same PRS explained more variance at 10 than 4 years (R(2) Δ:0.024; 0.002-0.078).

Conclusions: GCTA and PRS findings confirm twin-based results suggesting increasing genetic influence on adiposity during childhood despite substantial genetic stability.

Figure 1

Regression of mean age- and sex-adjusted BMI-SDS values at ages 4 and 10 years across the risk-allele scores. The histogram shows that the number of weighted obesity risk alleles was normally distributed in the sample. The solid black triangles show the mean age- and sex-adjusted BMI-SDS values at age 4 across the weighted risk-allele scores; the black diamonds show the mean age- and sex-adjusted BMI-SDS values at age 10 across the weighted risk-allele scores. The solid black line shows the regression line for age- and sex-adjusted BMI-SDS at age 4 predicted from the PRS (R² = 0.010; 95% CI: 4.3 e−09 to 0.042; P = 0.002). The dashed line shows the regression line for age- and sex-adjusted BMI-SDS at age 10 predicted from the PRS (R² = 0.034; 95% CI: 0.009-0.093; P < 0.001).

Figure 2

Comparison of twin- (solid black line), GCTA- (dashed line), and PRS-estimated (dotted line) heritability of BMI-SDS at age 4 and age 10. The variance explained by genetic effects increased from age 4 to age 10, using all three methods. The age-related increase in variance explained was significant for twin-estimated heritability and for the PRS; the GCTA-estimated heritability went from non-significant at age 4 to significant at age 10.