Abstract
Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
Highlights
Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function
This study examined variably methylated regions (VMRs), defined as regions of consecutive CpG-sites showing the highest variability across all methylation sites assessed on the Illumina Infinium HumanMethylation[450] BeadChip array
We investigated the influence of the prenatal environment and genotype on VMRs in the DNA of 2365 newborns within 4 different cohorts: Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restrictions (PREDO, cordblood)[30], the UCI cohort, the Drakenstein Child Health Study (DCHS, cordblood)[34,35] and the Norwegian Mother and Child Cohort Study (MoBa, cordblood36)
Summary
Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. Possible epigenetic changes as a consequence of prenatal stress are less well established[15] Some of these early differences in DNA methylation persist, attenuated, through childhood[11,16] and might be related to later symptoms and indicators of disease risk, including BMI during childhood[17,18] or substance use in adolescence[19]. In addition to the environment, the genome plays an important role in the regulation of DNA methylation To this end, the impact of genetic variation, especially of single nucleotide polymorphisms (SNPs) on DNA methylation in different tissues, has resulted in the discovery of a large number of methylation quantitative trait loci (meQTLs, i.e., SNPs significantly associated with DNA methylation status[20]). These studies highlight the importance of investigating the combination of environmental and genetic contributions to DNA methylation and their individual contribution
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