Lin X, Teh AL, Chen L, Lim IY, Tan PF, MacIsaac JL, Morin AM, Yap F, Tan KH, Saw SM, Lee YS, Holbrook JD, Godfrey KM, Meaney MJ, Kobor MS, Chong YS, Gluckman PD, Karnani N. “Choice of surrogate tissue influences neonatal EWAS findings”. BMC Med. 2017 Dec 5;15(1):211. doi: 10.1186/s12916-017-0970-x.
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.
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.
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.
The inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS.
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 .
This work was supported by the Translational Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease funded by the National Research Foundation (NRF) and administered by the National Medical Research Council (NMRC), Singapore – NMRC/TCR/004-NUS/2008. Additional funding is provided by Strategic Positioning Fund (SPF) awarded by the Agency for Science, Technology and Research (A*STAR), Singapore.
KMG is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre and by the European Union’s Seventh Framework Programme (FP7/2007-2013), projects EarlyNutrition and ODIN under grant agreement numbers 289346 and 613977.