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

• Type of Material: Article
• Authors: Lavinia Gordon, Murdoch Childrens Research Institute; Jihoon E. Joo, University of Melbourne; Joseph E. Powell, University of Queensland; Miina Ollikainen, University of Helsinki; Boris Novakovic, University of Melbourne; Xin Li, Murdoch Childrens Research Institute; Roberta Andronikos, University of Melbourne; Mark N. Cruickshank, Murdoch Childrens Research Institute; Karen Conneely, Emory University; Alicia Smith, Emory University; Reid S. Alisch, University of Wisconsin; Ruth Morley, Murdoch Childrens Research Institute; Peter M. Visscher, University of Queensland; Jeffrey M. Craig, University of Melbourne; Richard Saffery, University of Melbourne
• Language: English
• Date: 2012-08
• Publisher: Cold Spring Harbor Laboratory Press
• Publication Version: Final Published Version
• Copyright Statement: © 2012, Published by Cold Spring Harbor Laboratory Press
• License: Creative Commons Attribution-Noncommercial 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1101/gr.136598.111
• Title of Journal or Parent Work: Genome Research
• ISSN: 1088-9051
• Volume: 22
• Issue: 8
• Start Page: 1395
• End Page: 1406
• Grant/Funding Information: This work was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to J.C. and R.S.), the Bonnie Babes Foundation (grant number BBF20704 to E.J.), the Sigrid Juselius Foundation (to M.O.), the Academy of Finland (to M.O.), the Finnish Cultural Foundation (to M.O.), the Financial Markets Foundation for Children (grant no. 032-2007), and by the Victorian Government's Operational Infrastructure Support Program.
• Keywords: BIOTECHNOLOGY & APPLIED MICROBIOLOGY; FETAL ORIGINS; Life Sciences & Biomedicine; HUMAN GENOME; EPIGENETIC EPIDEMIOLOGY; BIRTH-WEIGHT; WIDE ASSOCIATION; CPG ISLAND SHORES; Biochemistry & Molecular Biology; MONOZYGOTIC TWINS; Science & Technology; Biotechnology & Applied Microbiology; ADULT DISEASE; ALLELE-SPECIFIC METHYLATION; Genetics & Heredity; BIOCHEMISTRY & MOLECULAR BIOLOGY; DEVELOPMENTAL ORIGINS; GENETICS & HEREDITY
• Research Categories: Health Sciences, Human Development; Biology, Genetics; Environmental Sciences

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-pairmethylation 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.