Heijmans BT, Kremer K, Tobi EW, Boomsma EI, Slagboom PE. Heritable rather than age-related environmental stochastic factors dominate variation in DNA methylation of the human IGF2/H10 locus. Hum Mol Genet 16: 547-554

VU University Amsterdam, Amsterdamo, North Holland, Netherlands
Human Molecular Genetics (Impact Factor: 6.39). 04/2007; 16(5):547-54. DOI: 10.1093/hmg/ddm010
Source: PubMed


Epigenetic variation may significantly contribute to the risk of common disease. Currently, little is known about the extent and causes of epigenetic variation. Here, we investigated the contribution of heritable influences and the combined effect of environmental and stochastic factors to variation in DNA methylation of the IGF2/H19 locus. Moreover, we tested whether this locus was subject to age-related degeneration of epigenetic patterns as was previously suggested for global methylation. We measured methylation of the H19 and IGF2 differentially methylated regions (DMRs) in 196 adolescent and 176 middle-aged twins using a recently developed mass spectrometry-based method. We observed substantial variation in DNA methylation across individuals, underscoring that DNA methylation is a quantitative trait. Analysis of data in monozygotic and dizygotic twins revealed that a significant part of this variation could be attributed to heritable factors. The heritability of methylation of individual CpG sites varied between 20 and 74% for the H19 DMR and was even higher, between 57 and 97%, for the IGF2 DMR. Remarkably, the combined influence of environmental and stochastic factors on DNA methylation was not greater in middle-age than in adolescence, suggesting a limited role for age-related degeneration of methylation patterns at this locus. Single nucleotide polymorphisms in the IGF2/H19 locus were significantly associated with DNA methylation of the IGF2 DMR (P = 0.004). A preliminary analysis suggested an association between H19 DMR methylation and body size (P < 0.05). Our study shows that variation in DNA methylation of the IGF2/H19 locus is mainly determined by heritable factors and single nucleotide polymorphisms (SNPs) in cis, rather than the cumulative effect of environmental and stochastic factors occurring with age.

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Available from: Bas Heijmans, Oct 06, 2014
    • "The IGF2 DMR0, IGF2AS and GNASXL amplicons used were previously described (Heijmans et al., 2007, Izzi et al., 2010, Izzi et al., 2012b). "
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    ABSTRACT: Epigenetic regulation of imprinted genes during embryonic development is influenced by the prenatal environment. Our aim was to examine the effect of maternal emotional stress and cortisol levels during pregnancy on methylation of imprinted genes IGF2 and GNASXL using umbilical cord blood DNA. Maternal depressed mood (Edinburgh Depression Scale; EDS), pregnancy-related anxiety (PRAQ) and cortisol day profiles were assessed throughout pregnancy. At birth, a cord blood sample (n = 80) was taken to study DNA methylation of IGF2 DMR0, IGF2AS and GNASXL using Sequenom EpiTYPER. Linear mixed models were used to examine the relationship between DNA methylation and maternal stress, while correcting for confounders. We also studied the association of DNA methylation with the child ponderal index at birth. We found a CpG-specific association of PRAQ subscales with IGF2 DMR0 (CpG5, p<0.0001) and GNASXL (CpG11, p=0.0003), while IGF2AS was associated with maternal EDS scores (CpG33, p=0.0003) and cortisol levels (CpG33, p=0.0006; CpG37-38, p=0.0005). However, there was no association of methylation with ponderal index at birth. In conclusion, maternal stress during pregnancy, as defined by cortisol measurements, EDS and PRAQ scores, is associated with DNA methylation of imprinted genes IGF2 and GNASXL. Our results provide further evidence that prenatal adversity can influence imprinted gene methylation, although future studies are needed to unravel the exact mechanisms. This article is protected by copyright. All rights reserved.
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    • "The analyses showed no meaningful associations , which further supports our contention that after correcting with the Houseman algorithm, cell heterogeneity had a minor impact on our blood DNA methylation data. Previous reports have demonstrated that genetic factors play an important role in the regulation of DNA methylation during aging (Heijmans et al. 2007; Coolen et al. 2011; Gertz et al. 2011; Bell et al. 2012). To determine whether the effect of genotype is different depending on the intrinsic behavior of the DNA changes during aging at each specific CpG site, we analyzed the DNA methylation status of MZ twins of different ages. "

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    • "c o m / l o c a t e / g e n e reported genomic regions where the methylation level is differentiated in obese individuals and varies with body-weight (Almen et al., 2012; Franks and Ling, 2010; Milagro et al., 2011; Wang et al., 2010). In contrast , methylation levels are also associated with genetic variations and can thus be governed, at least in part, by genetic factors (Heijmans et al., 2007). This is exemplified by a genome-wide longitudinal study of DNA methylation in an Icelandic population that confirms that inter-individual variation in methylation level depends on both genetic and environmental factors and that the extent of their influence differs between regions (Bjornsson et al., 2008). "
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    ABSTRACT: The combination of the Obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites were had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylation with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.
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