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

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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.
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.
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.
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
Issue number3
Early online date12 Mar 2018
Publication statusPublished - 1 Jun 2018

Bibliographical note

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).


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


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