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

doi:10.1093/hmg/ddx164

Abstract

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.

Highlights

Components of one carbon metabolism, which includes folate, and several B vitamins, play an important role in prenatal nutrition and have been implicated in a range of neurodevelopmental disorders in offspring [1]
We used a two-step Mendelian randomization (MR) approach to investigate whether prenatal exposure to maternal vitamin B12 levels is causally linked to offspring’s IQ at age 8 via changes in offspring’s DNA methylation
Our instrumental variable (IV) analysis suggests that maternal vitamin B12 status is causally associated with small differences in DNA methylation in the cord blood of offspring

Summary

Introduction

Components of one carbon metabolism, which includes folate, and several B vitamins, play an important role in prenatal nutrition and have been implicated in a range of neurodevelopmental disorders in offspring [1]. Adequate circulating vitamin B12 levels during pregnancy are associated with a decreased risk of neural tube defects [9] and there is evidence that maternal vitamin B12 status during pregnancy is associated with offspring cognition [10,11,12,13]. Emerging evidence suggests that maternal prenatal vitamin B12 status influences DNA methylation at the insulin-like growth factor-II locus and at a global level [14,15,16]

Methods

Results

Conclusion