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

  1. Richard Saffery2,3,12
  1. 1Bioinformatics Unit, Murdoch Childrens Research Institute (MCRI), Parkville, Victoria 3052, Australia;
  2. 2Cancer and Developmental Epigenetics Group, MCRI, Parkville, Victoria 3052, Australia;
  3. 3Department of Paediatrics, University of Melbourne, Victoria 3052, Australia;
  4. 4University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia;
  5. 5Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia;
  6. 6Hjelt Institute, Department of Public Health, FI-00014 University of Helsinki, Helsinki, Finland;
  7. 7Early Life Epigenetics Group, MCRI, Parkville, Victoria 3052, Australia;
  8. 8Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
  9. 9Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA;
  10. 10Department of Psychiatry, University of Wisconsin School of Medicine, Madison, Wisconsin 53719, USA;
  11. 11The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia

    1. ↵12 These authors contributed equally to this work.

    Abstract

    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.

    Footnotes

    • Received December 16, 2011.
    • Accepted April 26, 2012.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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    1. Published in Advance July 16, 2012, doi: 10.1101/gr.136598.111 Genome Res. 22: 1395-1406 © 2012, Published by Cold Spring Harbor Laboratory Press

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