Abstract
BackgroundDespite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood. The genetic heritability of DNA methylation has been estimated using twin pairs, although concern has been expressed whether the underlying assumption of equal common environmental effects are applicable due to intrauterine differences between monozygotic and dizygotic twins. We estimate the heritability of DNA methylation on peripheral blood leukocytes using Illumina HumanMethylation450 array using a family based sample of 614 people from 117 families, allowing comparison both within and across generations.ResultsThe correlations from the various available relative pairs indicate that on average the similarity in DNA methylation between relatives is predominantly due to genetic effects with any common environmental or zygotic effects being limited. The average heritability of DNA methylation measured at probes with no known SNPs is estimated as 0.187. The ten most heritable methylation probes were investigated with a genome-wide association study, all showing highly statistically significant cis mQTLs. Further investigation of one of these cis mQTL, found in the MHC region of chromosome 6, showed the most significantly associated SNP was also associated with over 200 other DNA methylation probes in this region and the gene expression level of 9 genes.ConclusionsThe majority of transgenerational similarity in DNA methylation is attributable to genetic effects, and approximately 20% of individual differences in DNA methylation in the population are caused by DNA sequence variation that is not located within CpG sites.
Highlights
Despite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood
We investigate the role of genetic heritability in the similarity of DNA methylation between generations using a family based sample of 614 individuals from 117 families consisting of twin pairs, their parents and siblings using DNA methylation measures on peripheral blood lymphocytes typed on Illumina HumanMethylation450 arrays
Genetic heritability is shown to be the major cause of similarity in DNA methylation levels among relatives when considering the average across the genome
Summary
Despite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood. The genetic heritability of DNA methylation has been estimated using twin pairs, concern has been expressed whether the underlying assumption of equal common environmental effects are applicable due to intrauterine differences between monozygotic and dizygotic twins. We estimate the heritability of DNA methylation on peripheral blood leukocytes using Illumina HumanMethylation450 array using a family based sample of 614 people from 117 families, allowing comparison both within and across generations. DNA methylation is a crucial epigenetic mark associated with regulation of regulating cellular processes including the silencing of gene expression, differentiation and maintaining genomic stability [1]. DNA methylation (along with other epigenetic changes) provides a biological link between an individual’s environmental exposures and their phenotype. The relative importance of genetic inheritance, epigenetic inheritance and common environmental influences to locus specific DNA methylation similarity among relatives has not been well estimated on a genome-wide scale
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