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

Eilis Hannon, Diana Schendel, Christine Marie Ladd-Acosta, Jakob Grove, Christine Søholm Hansen, David Michael Hougaard, Michaeline Bresnahan, Ole Mors, Mads Vilhelm Hollegaard, Marie Bækvad-Hansen, Mady Hornig, Preben Bo Mortensen, Anders D. Børglum, Thomas Werge, Marianne Giørtz Pedersen, Merete Nordentoft, Joseph D. Buxbaum, Daniele Daniele Fallin, Jonas Bybjerg-Grauholm, Abraham ReichenbergJonathan Mill

Research output: Contribution to journalArticle

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 ¼ 6.08 days; s.d. ¼ 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 27 . 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’.

Original languageEnglish (US)
Article number20180120
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Volume374
Issue number1770
DOIs
StatePublished - Apr 15 2019

Fingerprint

DNA methylation
DNA Methylation
Birth Weight
birth weight
neonates
Blood
gestational age
Smoking
Mothers
Newborn Infant
epigenetics
blood
Epigenomics
Obstetrics
Gestational Age
low birth weight
Surrogate Mothers
Parturition
Gene expression
drug therapy

Keywords

  • Birth weight
  • DNA methylation
  • Epigenome-wide association study
  • Gestational age
  • Maternal smoking
  • Mediation analysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight. / Hannon, Eilis; Schendel, Diana; Ladd-Acosta, Christine Marie; Grove, Jakob; Hansen, Christine Søholm; Hougaard, David Michael; Bresnahan, Michaeline; Mors, Ole; Hollegaard, Mads Vilhelm; Bækvad-Hansen, Marie; Hornig, Mady; Mortensen, Preben Bo; Børglum, Anders D.; Werge, Thomas; Pedersen, Marianne Giørtz; Nordentoft, Merete; Buxbaum, Joseph D.; Fallin, Daniele Daniele; Bybjerg-Grauholm, Jonas; Reichenberg, Abraham; Mill, Jonathan.

In: Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 374, No. 1770, 20180120, 15.04.2019.

Research output: Contribution to journalArticle

Hannon, E, Schendel, D, Ladd-Acosta, CM, Grove, J, Hansen, CS, Hougaard, DM, Bresnahan, M, Mors, O, Hollegaard, MV, Bækvad-Hansen, M, Hornig, M, Mortensen, PB, Børglum, AD, Werge, T, Pedersen, MG, Nordentoft, M, Buxbaum, JD, Fallin, DD, Bybjerg-Grauholm, J, Reichenberg, A & Mill, J 2019, 'Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight', Philosophical Transactions of the Royal Society B: Biological Sciences, vol. 374, no. 1770, 20180120. https://doi.org/10.1098/rstb.2018.0120
Hannon, Eilis ; Schendel, Diana ; Ladd-Acosta, Christine Marie ; Grove, Jakob ; Hansen, Christine Søholm ; Hougaard, David Michael ; Bresnahan, Michaeline ; Mors, Ole ; Hollegaard, Mads Vilhelm ; Bækvad-Hansen, Marie ; Hornig, Mady ; Mortensen, Preben Bo ; Børglum, Anders D. ; Werge, Thomas ; Pedersen, Marianne Giørtz ; Nordentoft, Merete ; Buxbaum, Joseph D. ; Fallin, Daniele Daniele ; Bybjerg-Grauholm, Jonas ; Reichenberg, Abraham ; Mill, Jonathan. / Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight. In: Philosophical Transactions of the Royal Society B: Biological Sciences. 2019 ; Vol. 374, No. 1770.
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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 ¼ 6.08 days; s.d. ¼ 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 27 . 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’.",
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T1 - Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight

AU - Hannon, Eilis

AU - Schendel, Diana

AU - Ladd-Acosta, Christine Marie

AU - Grove, Jakob

AU - Hansen, Christine Søholm

AU - Hougaard, David Michael

AU - Bresnahan, Michaeline

AU - Mors, Ole

AU - Hollegaard, Mads Vilhelm

AU - Bækvad-Hansen, Marie

AU - Hornig, Mady

AU - Mortensen, Preben Bo

AU - Børglum, Anders D.

AU - Werge, Thomas

AU - Pedersen, Marianne Giørtz

AU - Nordentoft, Merete

AU - Buxbaum, Joseph D.

AU - Fallin, Daniele Daniele

AU - Bybjerg-Grauholm, Jonas

AU - Reichenberg, Abraham

AU - Mill, Jonathan

PY - 2019/4/15

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N2 - 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 ¼ 6.08 days; s.d. ¼ 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 27 . 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’.

AB - 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 ¼ 6.08 days; s.d. ¼ 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 27 . 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’.

KW - Birth weight

KW - DNA methylation

KW - Epigenome-wide association study

KW - Gestational age

KW - Maternal smoking

KW - Mediation analysis

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