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Human Molecular Genetics Advance Access originally published online on March 5, 2007
Human Molecular Genetics 2007 16(5):547-554; doi:10.1093/hmg/ddm010
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus

Bastiaan T. Heijmans1,*, Dennis Kremer1, Elmar W. Tobi1, Dorret I. Boomsma2 and P. Eline Slagboom1

1 Molecular Epidemiology Section, Leiden University Medical Centre, Leiden 2333 ZC, The, Netherlands and 2 Biological Psychology, Vrije Universiteit, Amsterdam 1081 BT, The, Netherlands

* To whom correspondence should be addressed at: Molecular Epidemiology Section, Leiden University Medical Centre, Postal Zone S-05-P, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel: +31 715269785; Fax: +31 715268280; Email: b.t.heijmans{at}lumc.nl

Received December 7, 2006; Accepted January 26, 2007

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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