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Philos Trans R Soc Lond B Biol Sci. 2019 Apr 15;374(1770):20180120. doi: 10.1098/rstb.2018.0120.

Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight.

Author information

1
1 University of Exeter Medical School, University of Exeter , Exeter , UK.
2
2 Department of Public Health, Aarhus University , Aarhus , Denmark.
3
3 National Centre for Register-Based Research, Aarhus University , Aarhus , Denmark.
4
8 The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH , Aarhus , Denmark.
5
9 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD , USA.
6
10 Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD , USA.
7
4 Centre for Integrative Sequencing, iSEQ, Aarhus University , Aarhus , Denmark.
8
5 Department of Biomedicine - Human Genetics, Aarhus University , Aarhus , Denmark.
9
6 Bioinformatics Research Centre, Aarhus University , Aarhus , Denmark.
10
12 Centre for Genomics and Personalized Medicine , Aarhus , Denmark.
11
13 Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut , Copenhagen , Denmark.
12
14 Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services , Copenhagen , Denmark.
13
15 Center for Infection and Immunity, Columbia University Mailman School of Public Health , New York, NY , USA.
14
17 Psychosis Research Unit, Aarhus University Hospital , Risskov , Denmark.
15
16 Department of Epidemiology, Columbia University Mailman School of Public Health , New York, NY , USA.
16
7 Centre for Integrated Register-based Research, Aarhus University , Aarhus , Denmark.
17
18 Department of Clinical Medicine, Mental Health Center Copenhagen, University of Copenhagen , Copenhagen , Denmark.
18
19 Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen , Copenhagen , Denmark.
19
20 Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY , USA.
20
11 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD , USA.

Abstract

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10-7. Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

KEYWORDS:

DNA methylation; birth weight; epigenome-wide association study; gestational age; maternal smoking; mediation analysis

PMID:
30966880
PMCID:
PMC6460077
[Available on 2020-04-15]
DOI:
10.1098/rstb.2018.0120

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