Prenatal famine and genetic variation are independently and additively associated with DNA methylation at regulatory loci within IGF2/H19.

Elmar W Tobi,Jenny Van Dongen,Aryeh D Stein,P Eline Slagboom,Bastiaan T Heijmans,Dennis Kremer,L H Lumey,Hein Putter,Frank Lyko

doi:10.1371/journal.pone.0037933

Abstract

Both the early environment and genetic variation may affect DNA methylation, which is one of the major molecular marks of the epigenome. The combined effect of these factors on a well-defined locus has not been studied to date. We evaluated the association of periconceptional exposure to the Dutch Famine of 1944–45, as an example of an early environmental exposure, and single nucleotide polymorphisms covering the genetic variation (tagging SNPs) with DNA methylation at the imprinted IGF2/H19 region, a model for an epigenetically regulated genomic region. DNA methylation was measured at five differentially methylated regions (DMRs) that regulate the imprinted status of the IGF2/H19 region. Small but consistent differences in DNA methylation were observed comparing 60 individuals with periconceptional famine exposure with unexposed same-sex siblings at all IGF2 DMRs (PBH<0.05 after adjustment for multiple testing), but not at the H19 DMR. IGF2 DMR0 methylation was associated with IGF2 SNP rs2239681 (PBH = 0.027) and INS promoter methylation with INS SNPs, including rs689, which tags the INS VNTR, suggesting a mechanism for the reported effect of the VNTR on INS expression (PBH = 3.4×10−3). Prenatal famine and genetic variation showed similar associations with IGF2/H19 methylation and their contributions were additive. They were small in absolute terms (<3%), but on average 0.5 standard deviations relative to the variation in the population. Our analyses suggest that environmental and genetic factors could have independent and additive similarly sized effects on DNA methylation at the same regulatory site.

Highlights

The epigenome consists of inter-related layers of molecular marks on the DNA that represent non-genetic, but stable and mitotically heritable information determining the gene-expression potential of a genomic region [1]
Information on the individual CpG dinucleotides measured within each locus is given in table S2
We studied the relations between periconceptional famine exposure, genetic variation and DNA methylation at differentially methylated regions (DMRs) in the imprinted insulin-like growth factor 2 (IGF2)/H19 region

Summary

Introduction

The epigenome consists of inter-related layers of molecular marks on the DNA that represent non-genetic, but stable and mitotically heritable information determining the gene-expression potential of a genomic region [1]. Studies in animal models show that environmental factors during early development can cause persistent epigenetic changes in DNA methylation that are associated with disease-related phenotypes [2,3]. This suggests that the prenatal environment (‘nurture’) can persistently influence the expression of DNA sequences (‘nature’) [4]. Recent studies stress that variation in DNA methylation is primarily influenced by genetic variation [5] and that the DNA sequence itself dictates the DNA methylation state of a locus [6]. We at least are not aware of any such studies

Methods

Results

Conclusion