Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

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.

Biological embedding of experience: A primer on epigenetics

“…Genetic variants in FKBP5 influence local chromatin structure and mC levels, which correlate with measures of brain structure (hippocampal volume) and PTSD symptoms in individuals exposed to childhood trauma (27). Similarly, Teh et al (65) showed that the interaction of local genetic variants and aspects of the prenatal environment best explained variation in mC at 75% of genomic regions in human umbilical cord samples, a finding that is consistent with recent findings in neonatal blood (66). Such allele-specific epigenetic effects may provide a biological mechanism to explain gene-byenvironment interactions (27).…”

Genes and environments, development and time

“…These results suggest the need for studies that integrate analyses of both DNA sequence and DNA methylation. The findings of Teh et al (34) are bolstered by Czamara et al (35), who investigated the relative contributions of prenatal environmental factors and SNPs on DNA methylation at variably methylated regions in neonatal blood, in four independent cohorts (n = 2,365).…”

Epigenetics and depression

“…Notably, both models (G+E and GxE) were enriched for DMRs associated with GWAS of psychiatric disease, including MDD. 68 In another mechanistic study of GxE interactions driving epigenetic modifications, Klengel et al 69 identified an interaction between a variant (rs1360780) located in an enhancer region in FK506 binding protein 5 gene (FKBP5) and childhood trauma on DNA methylation of FKBP5 in peripheral blood cells. FKBP5 is an important regulator of the HPA axis and is involved in a negative feedback loop to terminate the stress response.…”