Epigenetic gestational age acceleration and indicators of BMI trajectories in childhood

Positive epigenetic gestational age acceleration, an epigenetic gestational age higher than the clinical gestational age, has been associated with higher birthweight and lower weight from 5 years onwards. We investigated the associations of epigenetic gestational age acceleration with age and BMI at adiposity peak and rebound to better understand epigenetic mechanisms associated with childhood BMI trajectories. DNA methylation, adiposity peak and adiposity rebound were available in 157 and 1247 children of the EDEN and Generation R Studies, respectively. We used linear regression models to test associations of epigenetic gestational age acceleration, estimated using the Bohlin and Knight clocks, with age and BMI at adiposity peak and rebound in both studies, and meta-analysed the results. Models were adjusted for maternal age, maternal and paternal education, maternal and paternal BMI, gestational weight gain, maternal smoking during pregnancy, child sex, and cell types. Multiple imputation was used to deal with missing values for covariates. In the meta-analysis, a higher raw epigenetic gestational age acceleration was associated with a later age at adiposity peak with an increase of one week in epigenetic gestational age acceleration being associated with 3.96 days later age at adiposity peak [95% confidence interval: 1.43; 6.49], and with a lower BMI at adiposity rebound (β[CI95%] =-0.08 [-0.13; -0.02] kg/m 2 ). No associations were found with BMI at adiposity peak or age at adiposity rebound. In conclusion, positive raw epigenetic gestational age acceleration was associated with later age at adiposity peak and lower BMI at adiposity rebound. Residual acceleration showed no associations, suggesting that shared variance with clinical gestational age may partly explain the findings. Further studies are needed to better understand whether and how epigenetic gestational age acceleration contributes to early programming of adiposity trajectories.