The association of DNA methylation with body mass index: distinguishing between predictors and biomarkers

Abstract

Background: DNA methylation is associated with body mass index (BMI), but it is not clear if methylation scores are biomarkers for extant BMI or predictive of future BMI. Here, we explore the causal nature and predictive utility of DNA methylation measured in peripheral blood with BMI and cardiometabolic traits. Methods: Analyses were conducted across the life course using the ARIES cohort of mothers (n = 792) and children (n = 906), for whom DNA methylation and genetic profiles and BMI at multiple time points (3 in children at birth, in childhood and in adolescence; 2 in mothers during pregnancy and in middle age) were available. Genetic and DNA methylation scores for BMI were derived using published associations between BMI and DNA methylation and genotype. Causal relationships between methylation and BMI were assessed using Mendelian randomisation and cross-lagged models. Results: The DNA methylation scores in adult women explained 10% of extant BMI variance. However, less extant variance was explained by scores generated in the same women during pregnancy (2% BMI variance) and in older children (15-17 years; 3% BMI variance). Similarly, little extant variance was explained in younger children (at birth and at 7 years; 1% and 2%, respectively). These associations remained following adjustment for smoking exposure and education levels. The DNA methylation score was found to be a poor predictor of future BMI using linear and cross-lagged models, suggesting that DNA methylation variation does not cause later variation in BMI. However, there was some evidence to suggest that BMI is predictive of later DNA methylation. Mendelian randomisation analyses also support this direction of effect, although evidence is weak. Finally, we find that DNA methylation scores for BMI are associated with extant cardiometabolic traits independently of BMI and genetic score. Conclusion: The age-specific nature of DNA methylation associations with BMI, lack of causal relationship and limited predictive ability of future BMI indicate that DNA methylation is likely influenced by BMI and might more accurately be considered a biomarker of BMI and related outcomes rather than a predictor. Future epigenome-wide association studies may benefit from further examining associations between early DNA methylation and later health outcomes.

Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight

“…[ 51 ], we did not identify strong direct associations between childhood methylation at these CpGs and later BMI. They did however identify associations between a DNAm score for BMI and health outcomes where BMI is a risk factor, suggesting methylation may have more utility as a biomarker of BMI-related morbidity than as a predictor of BMI itself [ 51 ].…”

“…Thus, if rapid growth was associated with DNA changes in this subset of CpGs, this perhaps would have been more likely to have been as a consequence of changes in BMI. Indeed, current evidence suggests that the direction of the effect is from BMI to DNAm [ 12 , 51 ]; therefore RWG (i.e. early life increases in BMI) associated DNAm changes may also be consequential of the phenotype rather than causal.…”

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

“…However, NFBC1966 and YFS replication cohorts showed smaller effect sizes than those found in the discovery cohort, perhaps due to the younger age and healthier status of NFBC1966 and YFS participants. Additionally, cross-sectional studies do not readily provide information on causation in the context of DNA methylation, although recent studies imply an effect of lipid levels on DNA methylation rather than vice versa [ 24 ], and DNA methylation has often been considered a biomarker rather than a predictor [ 20 , 24 , 25 , 29 , 31 , 32 ]. Mendelian randomization studies involving meta-analyses of studies of larger sample sizes than investigated here are needed to unravel the causal structures of the associations presented in this work [ 30 ].…”

“…While DNA methylation studies have highlighted several robustly replicated methylation markers of cardiometabolic phenotypes [14][15][16][17][18][19][20][21][22][23], the full causal interplay is unknown. However, it has been proposed that most causal changes in methylation are a consequence rather than a cause of dyslipidemia and body mass index (BMI), therefore indicating that methylation may be more a biomarker of prevalent conditions rather than a predictor of incident conditions [20,24,25,[29][30][31][32].…”

Genome-wide methylation data improves dissection of the effect of smoking on body mass index

“…Here we selected a subset of CpG sites with moderate to small heritability (lower than 40%, Supplementary Table 9) and we modelled them jointly with a genomic similarity matrix, making it unlikely that the variance picked up by the methylation matrix is genetic in nature. While most changes in methylation at these CpG sites are thought to be causally driven by smoking 19 , associations between methylation and other complex traits, such as BMI, are less well characterised and mostly likely to be reversely caused 48 (i.e., BMI affecting methylation), however, since our aim was to use methylation as a proxy for the environment, causality does not impact the conclusion of the study. It is, however, important to notice the variable nature of the methylation data, which will change during the life course of individuals unlike the genetics of the individuals, making the inclusion of methylation, measured far back in time, less relevant in a prediction framework 49 .…”