Replicating associations between DNA methylation and body mass index in a longitudinal sample of older twins

Background: There is an important interplay between epigenetic factors and body weight, and previous work has identified ten sites where DNA methylation is robustly associated with body mass index (BMI) cross-sectionally. However, interpretation of the associations is complicated by the substantial changes in BMI often occurring in late-life, and the fact that methylation is often driven by genetic variation. This study therefore investigated the longitudinal association between these ten sites and BMI from midlife to late-life, and whether associations persist after controlling for genetic factors. Methods: We used data from 535 individuals (mean age 68) in the Swedish Adoption/Twin Study of Aging (SATSA) with longitudinal measures of both DNA methylation from blood samples and BMI, spanning up to 20 years. Methylation levels were measured with the Infinium Human Methylation 450K or Infinium MethylationEpic array, with seven of the ten sites passing quality control. Latent growth curve models were applied to investigate longitudinal associations between methylation and BMI, and between–within models to study associations within twin pairs, thus adjusting for genetic factors. Results: Baseline DNA methylation levels at five of the seven sites were associated with BMI level at age 65 (cg00574958 [CPT1A]; cg11024682 [SREBF1]), and/or change (cg06192883 [MYO5C]; cg06946797 [RMI2]; cg08857797 [VPS25]). For four of the five sites, the associations remained comparable within twin pairs. However, the effects of cg06192883 were substantially attenuated within pairs. No change in DNA methylation was detected for any of the seven evaluated sites. Conclusion: Five of the seven sites investigated were associated with late-life level and/or change in BMI. The effects for four of the sites remained similar when examined within twin pairs, indicating that the associations are mainly environmentally driven. However, the substantial attenuation in the association between cg06192883 and late-life BMI within pairs points to the importance of genetic factors in this association