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BMC Med. 2017 Dec 5;15(1):211. doi: 10.1186/s12916-017-0970-x.

Choice of surrogate tissue influences neonatal EWAS findings.

Author information

1
Singapore Institute for Clinical Sciences, A*STAR, Singapore, 117609, Singapore.
2
Duke NUS Medical School, Singapore, 169857, Singapore.
3
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
4
KK Women's and Children's Hospital, Singapore, 229899, Singapore.
5
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 117597, Singapore.
6
Singapore Eye Research Institute, Singapore, 169856, Singapore.
7
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
8
Division of Paediatric Endocrinology and Diabetes, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, 119228, Singapore.
9
NIHR Biomedical Research Centre, University of Southampton, Southampton, SO16 6YD, UK.
10
MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK.
11
Ludmer Centre for Neuroinformatics and Mental Health, Douglas University Mental Health Institute, McGill University, Montreal, Quebec, H4H 1R3, Canada.
12
Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
13
Centre for Human Evolution, Adaptation and Disease, Liggins Institute, University of Auckland, Auckland, 1142, New Zealand.
14
Singapore Institute for Clinical Sciences, A*STAR, Singapore, 117609, Singapore. neerja_karnani@sics.a-star.edu.sg.
15
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore. neerja_karnani@sics.a-star.edu.sg.

Abstract

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 .

KEYWORDS:

DNA methylation; Epigenome-wide association study; Genotype; Neonate; Prenatal factors; Tissue-specificity

PMID:
29202839
PMCID:
PMC5715509
DOI:
10.1186/s12916-017-0970-x
[Indexed for MEDLINE]
Free PMC Article

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