Abstract
BackgroundEpigenomes 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.MethodsIn 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.ResultsNeonatal 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.ConclusionsThe inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS.Trial registrationThis 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.
Highlights
Epigenomes are tissue specific and 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
We investigated individual saturated fatty acids myristic acid, palmitic acid, and stearic acid; monounsaturated fatty acids oleic acid and gondoic acid; n-3 Polyunsaturated fatty acid (PUFA) eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA); and n-6 PUFAs linoleic acid, dihomo-gamma-linolenic acid (DGLA), and n-6 arachidonic acid (AA)
Prenatal factor influences on DNA methylation We investigated whether inter-individual variation in DNA methylation in each tissue could be explained by prenatal factors
Summary
Epigenomes are tissue specific and 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. Epigenetic processes, such as DNA methylation, are important regulators of gene expression and play a vital role in human development and disease. Epigenome-wide association studies (EWAS) using neonate tissues can help interrogate the inter-relationship between these factors and enhance our understanding of the biological mechanisms underpinning disease predisposition and progression. Surrogate tissues, such as cord blood, cord tissue, placenta, or buccal epithelium, are used as proxies
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