Choice of surrogate tissue influences neonatal EWAS findings.

TitleChoice of surrogate tissue influences neonatal EWAS findings.
Publication TypeJournal Article
Year of Publication2017
AuthorsLin X, Teh ALing, Chen L, Lim IYubin, Tan PFang, MacIsaac JL, Morin AM, Yap F, Tan KHian, Saw SMei, Lee YSeng, Holbrook JD, Godfrey KM, Meaney MJ, Kobor MS, Chong YSeng, Gluckman PD, Karnani N
JournalBMC Med
Date Published2017 12 05
KeywordsCpG Islands, DNA, DNA Methylation, Epigenesis, Genetic, Female, Fetal Blood, Genome-Wide Association Study, Genotype, Gestational Age, Humans, Infant, Newborn, Male, Pregnancy, Prospective Studies, Umbilical Cord, Young Adult

BACKGROUND: Epigenomes are tissue specific and thus the choice of surrogate tissue can play a critical role in interpreting neonatal epigenome-wide association studies (EWAS) and in their extrapolation to target tissue. To develop a better understanding of the link between tissue specificity and neonatal EWAS, and the contributions of genotype and prenatal factors, we compared genome-wide DNA methylation of cord tissue and cord blood, two of the most accessible surrogate tissues at birth.METHODS: In 295 neonates, DNA methylation was profiled using Infinium HumanMethylation450 beadchip arrays. Sites of inter-individual variability in DNA methylation were mapped and compared across the two surrogate tissues at birth, i.e., cord tissue and cord blood. To ascertain the similarity to target tissues, DNA methylation profiles of surrogate tissues were compared to 25 primary tissues/cell types mapped under the Epigenome Roadmap project. Tissue-specific influences of genotype on the variable CpGs were also analyzed. Finally, to interrogate the impact of the in utero environment, EWAS on 45 prenatal factors were performed and compared across the surrogate tissues.RESULTS: Neonatal EWAS results were tissue specific. In comparison to cord blood, cord tissue showed higher inter-individual variability in the epigenome, with a lower proportion of CpGs influenced by genotype. Both neonatal tissues were good surrogates for target tissues of mesodermal origin. They also showed distinct phenotypic associations, with effect sizes of the overlapping CpGs being in the same order of magnitude.CONCLUSIONS: The inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS.TRIAL REGISTRATION: This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875 .

Alternate JournalBMC Med
PubMed ID29202839
PubMed Central IDPMC5715509
Grant ListFP7/2007-2013 / / National Institute for Health Research / International
MC_U147574226 / / Medical Research Council / United Kingdom
MC_UP_A620_1017 / / Medical Research Council / United Kingdom
MC_U147574222 / / Medical Research Council / United Kingdom
NMRC/TCR/004-NUS/2008 / / National Medical Research Council / International
MR/J000094/1 / / Medical Research Council / United Kingdom
Strategic Position Fund- Theme D / / A*STAR / International