DNA methylation marks associated with body composition in children from India and the Gambia - findings from the EMPHASIS study

BackgroundDifferences in body composition during childhood can influence long-term health, with notable links to cardiometabolic disorders in later life. While genetic associations with body composition traits are well-studied, less is known about the role of epigenetic mechanisms, particularly in low- and middle-income countries where the burden of cardiometabolic disease is high. We investigated links between DNA methylation and three compartments of body composition: fat mass, lean mass, and bone measures using data from children enrolled in the Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa (EMPHASIS) study. ResultsWe conducted an epigenome-wide association study (EWAS) of 11 body composition traits assessed through dual-energy X-ray absorptiometry in children from India (age = 5-7 years, n = 686) and The Gambia (age = 7-9 years, n = 289), with blood DNA methylation measured at approximately 800,000 CpGs sites on on the Illumina EPIC array. Cohort-specific analysis identified 15 unique differentially methylated CpGs (dmCpGs) associated with traits across all three compartments of body composition (p<3.6x10-8). Cross-cohort meta-analysis revealed 4 loci associated with lean mass and bone area. Notably, dmCpGs mapping to the SOCS3 gene, previously linked to height in Indian, African and European populations, were associated with lean mass and bone area in both the Indian cohort and combined meta-analyses. Region-level EWAS identified differentially methylated regions (DMRs), linked to lean mass and bone area mapping to SOCS3 and P4HB genes overlapping identified dmCpGs associated with the same phenotypes. Other DMRs mapped to genes including BPNT1, RNU5F-1, LTA, HIF1A, HIF1A-AS1, MTHFD1, and TRIM72 were associated with multiple traits. ConclusionWe report novel DNA methylation signatures associated with body composition traits in children from two low- and middle-income countries, highlighting a potential role for epigenetic mechanisms in shaping early-life body composition.