Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Bioinformatics Unit, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
Genome Research (Impact Factor: 14.63). 07/2012; 22(8):1395-406. DOI: 10.1101/gr.136598.111
Source: PubMed


Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.

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    • "To date, three EWAS have focused on MZ twins discordant for birth weight. The first profiled DNA methylation using the Infinium 27K array in 14 birth weight discordant MZ twin pairs (Gordon et al., 2012). One differential methylation signal was identified in the APOLD1 gene, which has previously been linked to metabolic phenotypes. "
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    ABSTRACT: Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to pre-disposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10-8), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.
    Twin Research and Human Genetics 11/2015; DOI:10.1017/thg.2015.76 · 2.30 Impact Factor
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    • "A number of studies based on limited numbers of twin pairs have shown significantly higher genome-wide average correlations in DNA methylation measures in monozygotic (MZ) twins compared to dizygotic (DZ) twins, indicating a significant genetic component underlying variation in DNA methylation [9]. Studies using the Illumina HumanMethylation27 array found average estimates of heritability of 0.18 and 0.19 in whole blood [10] and 0.12, 0.07 and 0.05 in cord blood mononuclear cells, umbilical vascular endothelial cells and placenta, respectively [11]. Both these studies used fewer than 20 of each MZ and DZ pairs in the estimation of heritability. "
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    ABSTRACT: Background 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, 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. Results The 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. Conclusions The 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.
    Genome Biology 05/2014; 15(5):R73. DOI:10.1186/gb-2014-15-5-r73 · 10.81 Impact Factor
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    • "This suggests the existence of an inherent process that is programmed at the genome level, and raises the possibility that this type of targeted de novo methylation may also occur during normal development in vivo. In this paper, we demonstrate that a similar epigenetic pathway is indeed associated with de novo methylation in both mouse and human placenta [39], [55], [56], [57]. Previous studies already showed that extraembryonic tissues also undergo generalized hypo-methylation [58]. "
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    ABSTRACT: Both mouse and human embryonic stem cells can be differentiated in vitro to produce a variety of somatic cell types. Using a new developmental tracing approach, we show that these cells are subject to massive aberrant CpG island de novo methylation that is exacerbated by differentiation in vitro. Bioinformatics analysis indicates that there are two distinct forms of abnormal de novo methylation, global as opposed to targeted, and in each case the resulting pattern is determined by molecular rules correlated with local pre-existing histone modification profiles. Since much of the abnormal methylation generated in vitro appears to be stably maintained, this modification may inhibit normal differentiation and could predispose to cancer if cells are used for replacement therapy. Excess CpG island methylation is also observed in normal placenta, suggesting that this process may be governed by an inherent program.
    PLoS ONE 05/2014; 9(5):e96090. DOI:10.1371/journal.pone.0096090 · 3.23 Impact Factor
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