The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen folic acid supplementation trial (AFAST)

Rebecca Richmond, Gemma Sharp, Georgia Herbert, Charlotte Atkinson, Caroline Taylor, Sohinee Bhattachrya, Doris Campbell, Marion Hall, Nabila Kazmi, Tom Gaunt, Wendy McArdle, Susan Ring, George Davey Smith, Andrew R Ness, Caroline Relton

Research output: Contribution to journalArticle (Academic Journal)peer-review

50 Citations (Scopus)
392 Downloads (Pure)


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 28 ), 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. Key words: Epigenetic, AFAST, randomized controlled trial, longitudinal, epigenome-wide associationstudy, DNA methylation
Original languageEnglish
JournalInternational Journal of Epidemiology
Issue number3
Early online date12 Mar 2018
Publication statusE-pub ahead of print - 12 Mar 2018

Structured keywords

  • ICEP


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


Dive into the research topics of 'The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen folic acid supplementation trial (AFAST)'. Together they form a unique fingerprint.

Cite this