Differentially methylated regions interrogated for metastable epialleles associate with offspring adiposity

<b>Aim:</b> Assess if cord blood differentially methylated regions (DMRs) representing human metastable epialleles (MEs) associate with offspring adiposity in 588 maternal-infant dyads from the Colorado Health Start Study. <b>Materials &amp; methods:</b> DNA methylation was assessed via the Illumina 450K array (~439,500 CpG sites). Offspring adiposity was obtained via air displacement plethysmography. Linear regression modeled the association of DMRs potentially representing MEs with adiposity. <b>Results &amp; conclusion:</b> We identified two potential MEs, <i>ZFP57</i>, which associated with infant adiposity change and <i>B4GALNT4</i>, which associated with infancy and childhood adiposity change. Nine DMRs annotating to genes that annotated to MEs associated with change in offspring adiposity (false discovery rate &lt;0.05). Methylation of approximately 80% of DMRs identified associated with decreased change in adiposity. Differences in obesity risk may appear as early as infancy, suggesting that developmental factors driving obesity are operating very early in life. There is emerging evidence from human studies of the potential for epigenetic signatures, namely DNA methylation (DNAm), to serve as predictive biomarkers of obesity risk. Human metastable epialleles (MEs) are unique genomic regions established during early embryogenesis that show systemic interindividual variation and stability across different tissues and may be influenced by preconceptional exposures. DNAm of MEs has been suggested to play a role in energy balance and has previously been associated with obesity in adult and pediatric populations. We explored differentially methylated regions potentially representative of MEs from the literature as potential biomarkers of adiposity at birth and adiposity change in infancy and childhood and attempted to identify a persistent association of these in cord blood with adiposity change throughout infancy and early childhood. We found associations between offspring change in adiposity in infancy and childhood and newborn cord blood DNAm of nine DMRs that annotated to genes, which also annotated to MEs referenced in the literature. The annotated genes are biologically relevant and related to obesity risk, nutrient metabolism and neuroendocrine energy balance. We found lower methylation of one DMR and a putative ME, <i>ZFP57</i>, to be associated with an overall increased change in adiposity from birth to 5 months only. The gene is proposed to promote dysregulation of imprinting gene networks and body weight control and has been identified as a metastable epiallele by others. We identified one DMR annotated to <i>B4GALNT4</i> that associated with change in offspring adiposity from birth to 5 months and from 5 months to 5 years of age. This was the only gene annotated to a DMR that was associated with adiposity change in both age intervals in our analysis. <i>B4GALNT4</i> has a role in the biosynthesis and transfer of N-acetlygalactosamine residues to <i>N-</i> and <i>O-</i>glycans present on glycoproteins found on mammalian pituitary and hypothalamic hormones and peptides such as <i>POMC</i>, a regulator of energy intake and expenditure. Furthermore, the kilobase distance of <i>B4GALNT4</i> from the ME annotated to the same gene as referenced in Gunasekara et al. may support its potential as a ME, though more studies would be needed. Using cord blood, we have identified potential, biologically plausible, epigenetic biomarkers for adiposity change during two separate critical periods of development considered important for assessing rapid growth and risk of obesity that may be of use in future investigations. However, skepticism of our results is due given lack of validation with the alternative DMR identification method employed (i.e., bumphunter) in addition to the inability to replicate findings using a different cohort.