The long-term impact of folic acid in pregnancy on offspring DNA methylation

follow-up of the Aberdeen folic acid supplementation trial (AFAST)

Rebecca C. Richmond, Gemma C. Sharp, Georgia Herbert, Charlotte Atkinson, Caroline Taylor, Sohinee Bhattacharya, Doris Campbell, Marion Hall, Nabila Kazmi, Tom Gaunt, Wendy McArdle, Susan Ring, George Davey Smith, Andy Ness, Caroline L. Relton

Research output: Contribution to journalArticle

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Abstract

Background
It has been proposed that maternal folic acid supplement use may alter DNA methylation patterns of the offspring during the in utero period, which could influence development and later life health outcomes. Evidence from human studies suggests a role of prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood.
Methods
To better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen folic acid supplementation trial (AFAST – a trial of two different doses, 0.2mg and 5mg, folic acid versus placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single site and differentially methylated region analysis were performed.
Results
We found an association at cg09112514 (p=4.03x10-9), a CpG located in the 5’ untranslated region of PDGFRA, in the main analysis comparing the intervention arms (low (0.2mg) and high dose (5mg) folic acid combined (N=43)) versus placebo (N=43). Furthermore, a dose-response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome which were differentially methylated in response to the intervention (Sidak P-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2-1. While cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8.
Conclusions
The results of this study suggest that maternal folic acid supplement use is associated with changes in DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.
Original languageEnglish
Pages (from-to)928-937
Number of pages10
JournalInternational Journal of Epidemiology
Volume47
Issue number3
Early online date12 Mar 2018
DOIs
Publication statusPublished - 1 Jun 2018

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DNA Methylation
Folic Acid
Pregnancy
Mothers
Methylation
Placebos
5' Untranslated Regions
Saliva
Epigenomics
Embryonic Development
Cell Proliferation
Genome
Health

Keywords

  • Epigenetic
  • AFAST
  • randomized-controlled trial
  • longitudinal
  • epigenome-wide association study
  • DNA methylation

Cite this

The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST). / Richmond, Rebecca C.; Sharp, Gemma C.; Herbert, Georgia; Atkinson, Charlotte; Taylor, Caroline; Bhattacharya, Sohinee; Campbell, Doris; Hall, Marion; Kazmi, Nabila; Gaunt, Tom; McArdle, Wendy; Ring, Susan; Smith, George Davey; Ness, Andy; Relton, Caroline L.

In: International Journal of Epidemiology, Vol. 47, No. 3, 01.06.2018, p. 928-937.

Research output: Contribution to journalArticle

Richmond, RC, Sharp, GC, Herbert, G, Atkinson, C, Taylor, C, Bhattacharya, S, Campbell, D, Hall, M, Kazmi, N, Gaunt, T, McArdle, W, Ring, S, Smith, GD, Ness, A & Relton, CL 2018, 'The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen folic acid supplementation trial (AFAST)', International Journal of Epidemiology, vol. 47, no. 3, pp. 928-937. https://doi.org/10.1093/ije/dyy032
Richmond, Rebecca C. ; Sharp, Gemma C. ; Herbert, Georgia ; Atkinson, Charlotte ; Taylor, Caroline ; Bhattacharya, Sohinee ; Campbell, Doris ; Hall, Marion ; Kazmi, Nabila ; Gaunt, Tom ; McArdle, Wendy ; Ring, Susan ; Smith, George Davey ; Ness, Andy ; Relton, Caroline L. / The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST). In: International Journal of Epidemiology. 2018 ; Vol. 47, No. 3. pp. 928-937.
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abstract = "BackgroundIt has been proposed that maternal folic acid supplement use may alter DNA methylation patterns of the offspring during the in utero period, which could influence development and later life health outcomes. Evidence from human studies suggests a role of prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood.MethodsTo better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen folic acid supplementation trial (AFAST – a trial of two different doses, 0.2mg and 5mg, folic acid versus placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single site and differentially methylated region analysis were performed.ResultsWe found an association at cg09112514 (p=4.03x10-9), a CpG located in the 5’ untranslated region of PDGFRA, in the main analysis comparing the intervention arms (low (0.2mg) and high dose (5mg) folic acid combined (N=43)) versus placebo (N=43). Furthermore, a dose-response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome which were differentially methylated in response to the intervention (Sidak P-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2-1. While cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8.ConclusionsThe results of this study suggest that maternal folic acid supplement use is associated with changes in DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.",
keywords = "Epigenetic, AFAST, randomized-controlled trial, longitudinal, epigenome-wide association study, DNA methylation",
author = "Richmond, {Rebecca C.} and Sharp, {Gemma C.} and Georgia Herbert and Charlotte Atkinson and Caroline Taylor and Sohinee Bhattacharya and Doris Campbell and Marion Hall and Nabila Kazmi and Tom Gaunt and Wendy McArdle and Susan Ring and Smith, {George Davey} and Andy Ness and Relton, {Caroline L.}",
note = "Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).",
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TY - JOUR

T1 - The long-term impact of folic acid in pregnancy on offspring DNA methylation

T2 - follow-up of the Aberdeen folic acid supplementation trial (AFAST)

AU - Richmond, Rebecca C.

AU - Sharp, Gemma C.

AU - Herbert, Georgia

AU - Atkinson, Charlotte

AU - Taylor, Caroline

AU - Bhattacharya, Sohinee

AU - Campbell, Doris

AU - Hall, Marion

AU - Kazmi, Nabila

AU - Gaunt, Tom

AU - McArdle, Wendy

AU - Ring, Susan

AU - Smith, George Davey

AU - Ness, Andy

AU - Relton, Caroline L.

N1 - Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).

PY - 2018/6/1

Y1 - 2018/6/1

N2 - BackgroundIt has been proposed that maternal folic acid supplement use may alter DNA methylation patterns of the offspring during the in utero period, which could influence development and later life health outcomes. Evidence from human studies suggests a role of prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood.MethodsTo better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen folic acid supplementation trial (AFAST – a trial of two different doses, 0.2mg and 5mg, folic acid versus placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single site and differentially methylated region analysis were performed.ResultsWe found an association at cg09112514 (p=4.03x10-9), a CpG located in the 5’ untranslated region of PDGFRA, in the main analysis comparing the intervention arms (low (0.2mg) and high dose (5mg) folic acid combined (N=43)) versus placebo (N=43). Furthermore, a dose-response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome which were differentially methylated in response to the intervention (Sidak P-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2-1. While cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8.ConclusionsThe results of this study suggest that maternal folic acid supplement use is associated with changes in DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.

AB - BackgroundIt has been proposed that maternal folic acid supplement use may alter DNA methylation patterns of the offspring during the in utero period, which could influence development and later life health outcomes. Evidence from human studies suggests a role of prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood.MethodsTo better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen folic acid supplementation trial (AFAST – a trial of two different doses, 0.2mg and 5mg, folic acid versus placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single site and differentially methylated region analysis were performed.ResultsWe found an association at cg09112514 (p=4.03x10-9), a CpG located in the 5’ untranslated region of PDGFRA, in the main analysis comparing the intervention arms (low (0.2mg) and high dose (5mg) folic acid combined (N=43)) versus placebo (N=43). Furthermore, a dose-response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome which were differentially methylated in response to the intervention (Sidak P-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2-1. While cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8.ConclusionsThe results of this study suggest that maternal folic acid supplement use is associated with changes in DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.

KW - Epigenetic

KW - AFAST

KW - randomized-controlled trial

KW - longitudinal

KW - epigenome-wide association study

KW - DNA methylation

U2 - 10.1093/ije/dyy032

DO - 10.1093/ije/dyy032

M3 - Article

VL - 47

SP - 928

EP - 937

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

IS - 3

ER -