Exploring a causal role of DNA methylation in the relationship between maternal vitamin B12 during pregnancy and child's IQ at age 8, cognitive performance and educational attainment: A two-step Mendelian randomization study

Doretta Caramaschi, Gemma C Sharp, Ellen A Nohr, Katie Berryman, Sarah J Lewis, George Davey Smith, Caroline L Relton

Research output: Contribution to journalJournal articleResearchpeer-review

150 Downloads (Pure)


An adequate intake of vitamin B12 during pregnancy plays an important role in offspring neurodevelopment, potentially via epigenetic processes. We used a two-step Mendelian randomization approach to assess whether DNA methylation plays a mediating and causal role in associations between maternal vitamin B12 status and offspring's cognition. Firstly, we estimated the causal effect of maternal vitamin B12 levels on cord blood DNA methylation using the maternal FUT2 genotypes rs492602:A > G and rs1047781:A > T as proxies for circulating vitamin B12 levels in the Avon Longitudinal Study of Parents and Children (ALSPAC) and we tested the observed associations in a replication cohort. Secondly, we estimated the causal effect of DNA methylation on IQ using the offspring genotype at sites close to the methylated CpG site as a proxy for DNA methylation in ALSPAC and in a replication sample. The first step Mendelian randomization estimated that maternal vitamin B12 had a small causal effect on DNA methylation in offspring at three CpG sites, which was replicated for one of the sites. The second step Mendelian randomization found weak evidence of a causal effect of DNA methylation at two of these sites on childhood performance IQ which was replicated for one of the sites. The findings support a causal effect of maternal vitamin B12 levels on cord blood DNA methylation, and a causal effect of vitamin B12-responsive DNA methylation changes on children's cognition. Some limitations were identified and future studies using a similar approach should aim to overcome such issues.

Original languageEnglish
JournalHuman Molecular Genetics
Issue number15
Pages (from-to)3001-3013
Publication statusPublished - 1. Aug 2017



  • Adult
  • Child
  • Cognition/drug effects
  • DNA Methylation/genetics
  • Epigenesis, Genetic/genetics
  • Family
  • Female
  • Fetal Blood/metabolism
  • Genotype
  • Humans
  • Intelligence Tests
  • Intelligence/drug effects
  • Longitudinal Studies
  • Male
  • Mendelian Randomization Analysis
  • Pregnancy
  • Prenatal Exposure Delayed Effects/genetics
  • Random Allocation
  • Vitamin B 12/metabolism

Cite this