Caramaschi Doretta, Sharp Gemma C, Nohr Ellen A, Berryman Katie, Lewis Sarah J, Davey Smith George, Relton Caroline L
Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine.
School of Oral and Dental Sciences, The Cleft Collective, University of Bristol, Bristol BS8 2BN, UK.
Hum Mol Genet. 2017 Aug 1;26(15):3001-3013. doi: 10.1093/hmg/ddx164.
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.
孕期充足摄入维生素B12对后代神经发育起着重要作用，可能是通过表观遗传过程实现的。我们采用两步孟德尔随机化方法来评估DNA甲基化在母体维生素B12状态与后代认知之间的关联中是否起中介和因果作用。首先，在阿冯父母与儿童纵向研究（ALSPAC）中，我们使用母体FUT2基因rs492602:A＞G和rs1047781:A＞T作为循环维生素B12水平的代理指标，估计母体维生素B12水平对脐带血DNA甲基化的因果效应，并在一个重复队列中检验观察到的关联。其次，在ALSPAC及其重复样本中，我们使用靠近甲基化CpG位点的后代基因型作为DNA甲基化的代理指标，估计DNA甲基化对智商的因果效应。第一步孟德尔随机化估计，母体维生素B12对后代三个CpG位点的DNA甲基化有较小的因果效应，其中一个位点得到了重复验证。第二步孟德尔随机化发现，这些位点中有两个位点的DNA甲基化对儿童操作智商有因果效应的证据较弱，其中一个位点得到了重复验证。这些发现支持母体维生素B12水平对脐带血DNA甲基化有因果效应，以及维生素B12反应性DNA甲基化变化对儿童认知有因果效应。我们识别出了一些局限性，未来采用类似方法的研究应旨在克服这些问题。
