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Abstract
DNA methylation is a key epigenetic mechanism involved in the developmental regulation of gene expression. Alterations in DNA methylation are established contributors to inter-individual phenotypic variation and have been associated with disease susceptibility. The degree to which changes in loci-specific DNA methylation are under the influence of heritable and environmental factors is largely unknown. In this study, we quantitatively measured DNA methylation across the promoter regions of the dopamine receptor 4 gene (DRD4), the serotonin transporter gene (SLC6A4/SERT) and the X-linked monoamine oxidase A gene (MAOA) using DNA sampled at both ages 5 and 10 years in 46 MZ twin-pairs and 45 DZ twin-pairs (total n=182). Our data suggest that DNA methylation differences are apparent already in early childhood, even between genetically identical individuals, and that individual differences in methylation are not stable over time. Our longitudinal-developmental study suggests that environmental influences are important factors accounting for interindividual DNA methylation differences, and that these influences differ across the genome. The observation of dynamic changes in DNA methylation over time highlights the importance of longitudinal research designs for epigenetic research.
Acknowledgements
This research received support from UK Medical Research Council grants G9806489, G0100527 and G0601483, US-NIH grants MH077874 and HD061298, and the London University Central Research Fund. Avshalom Caspi is a Royal Society-Wolfson Merit Award holder. Chloe Wong is a PhD student funded by the UK Medical Research Council. The authors declare no conflicts of interest.
Figures and Tables
Figure 1 Average DNA methylation level in DRD4, SERT and MAOA amplicons at ages 5 and 10 years. * Significant differences (p < 0.001) in average MAOA DNA methylation level between male and female children. MZ, monozygotic; DZ, dizygotic; MZM, monozygotic male; MZF, monozygotic female; DZM, dizygotic male; DZF, dizygotic female.
Figure 2 Longitudinal analysis of DRD4 DNA methylation in MZ and DZ twins. (A) Individual changes in average DRD4 DNA methylation between ages 5 and 10 years. (B) Inter-individual stability correlations for DRD4 DNA methylation, between ages 5 and 10 years. (C) MZ and DZ twin correlations for average DRD4 DNA methylation at age 5. (D) MZ and DZ twin correlations for average DRD4 DNA methylation at age 10. (E) MZ and DZ twin correlations for intraindividual change in DRD4 DNA methylation from age 5 to age 10 years.
Figure 3 Longitudinal analysis of SERT DNA methylation in MZ and DZ twins. (A) Individual changes in average SERT DNA methylation between ages 5 and 10 years. (B) Inter-individual stability correlations for SERT DNA methylation, between ages 5 and 10 years. (C) MZ and DZ twin correlations for average SERT DNA methylation at age 5. (D) MZ and DZ twin correlations for average SERT DNA methylation at age 10. (E) MZ and DZ twin correlations for intraindividual change in SERT DNA methylation from age 5 to age 10 years.
Figure 4 Longitudinal analysis of MAOA DNA methylation in MZ and DZ twins, stratified by sex. (A) Individual changes in average MAOA DNA methylation between ages 5 and 10 years. (B) Inter-individual stability correlations for MAOA DNA methylation, between ages 5 and 10 years. (C) MZ and DZ twin correlations for average MAOA DNA methylation at age 5. (D) MZ and DZ twin correlations for average MAOA DNA methylation at age 10. (E) MZ and DZ twin correlations for intraindividual change in MAOA DNA methylation from age 5 to age 10 years. MZM, monozygotic male; MZF, monozygotic female; DZM, dizygotic male; DZF, dizygotic female.
