Effect of maternal preconceptional and pregnancy micronutrient interventions on children’s DNA methylation: Findings from the EMPHASIS study

Abstract

Background Maternal nutrition in pregnancy has been linked to offspring health in early and later life, with changes to DNA methylation (DNAm) proposed as a mediating mechanism. Objective We investigated intervention-associated DNAm changes in children whose mothers participated in 2 randomized controlled trials of micronutrient supplementation before and during pregnancy, as part of the EMPHASIS (Epigenetic Mechanisms linking Preconceptional nutrition and Health Assessed in India and sub-Saharan Africa) study (ISRCTN14266771). Design We conducted epigenome-wide association studies with blood samples from Indian (n = 698) and Gambian (n = 293) children using the Illumina EPIC array and a targeted study of selected loci not on the array. The Indian micronutrient intervention was food based, whereas the Gambian intervention was a micronutrient tablet. Results We identified 6 differentially methylated CpGs in Gambians [2.5–5.0% reduction in intervention group, all false discovery rate (FDR) <5%], the majority mapping to ESM1, which also represented a strong signal in regional analysis. One CpG passed FDR <5% in the Indian cohort, but overall effect sizes were small (<1%) and did not have the characteristics of a robust signature. We also found strong evidence for enrichment of metastable epialleles among subthreshold signals in the Gambian analysis. This supports the notion that multiple methylation loci are influenced by micronutrient supplementation in the early embryo. Conclusions Maternal preconceptional and pregnancy micronutrient supplementation may alter DNAm in children measured at 7–9 y. Multiple factors, including differences between the nature of the intervention, participants, and settings, are likely to have contributed to the lack of replication in the Indian cohort. Potential links to phenotypic outcomes will be explored in the next stage of the EMPHASIS study.

Environmentally sensitive hotspots in the methylome of the early human embryo

“…However, we did find that half of SoC-CpGs had at least one associated mQTL, indicating the presence of independent additive effects of environment and genetics at these loci, as has been suggested previously at other loci sensitive to pre/periconceptional nutritional exposures 31,65 . We have previously argued that the definition of MEs should be extended to include genomic regions whose DNAm state is under partial but non-deterministic genetic influence in genetically heterogeneous human populations 14 , and we would argue that the above observations at SoC-CpGs that exhibit many of the characteristics of MEs support this.…”

“…450k Sentrix Column was included as an additional adjustment covariate for the ENID cohort since this was not robustly captured by any of the first 6 PCs (Supplementary Table 16). Child age was included as an additional adjustment covariate for the EMPHASIS cohort, since child ages ranged from 8 to 9 years, as was maternal nutritional intervention group (see Chandak et al 10 and Saffari et al 65 for further details).…”

“…Array-derived genotypes were pre-phased using SHAPEITv2 and imputation was performed using IMPUTEv2.3.2 on 1000 genomes phase 3 data. Further details are provided in Saffari et al 65 . SNPs with a MAF £ 10% were excluded, along with those with an IMPUTE 'info' metric £ 0.9, a stringent threshold to ensure maximum confidence in imputation quality.…”

Environmental Exposures around Conception: Developmental Pathways Leading to Lifetime Disease Risk

“…Preconception interventions with power for child health follow-up offer improved opportunities for success, for example in child growth [152,153]. Moreover, preconception supplementation also influenced the epigenome of children up to 9 years [154]. These new and emerging datasets authenticate the susceptibility of peri-conception environment from experimental research, and in turn, require new thinking on the social and educational policies to mediate key messages to adolescent women [155].…”

Associations of genetic scores for birth weight with newborn size and later anthropometric traits and cardiometabolic risk markers in South Asians

“…Trained research staff carried out newborn anthropometry within 10 days of birth. In the current study, we have used the child phenotype data at birth (anthropometry) and in early childhood (5-7-year follow-up), when detailed anthropometry, systolic and diastolic blood pressure, fasting and post-load glucose and insulin, and fasting LDL-and HDL-cholesterol and triglycerides were measured 30 . Maternal anthropometry, blood pressure and fasting plasma glucose and insulin concentrations were also measured at this follow-up.…”