DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis
DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis
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DOI：
10.1016/j.ajhg.2016.02.019
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发表时间：
2016-04-07
影响因子：
9.8
通讯作者：
London, Stephanie J.
中科院分区：
文献类型：
--
作者：
Joubert, Bonnie R.;Felix, Janine F.;London, Stephanie J.
表观遗传修饰，包括DNA甲基化，代表了环境对人类疾病影响的潜在机制。孕妇在怀孕期间吸烟仍然是一个重要的公共卫生问题，它以各种方式影响儿童健康，并可能产生终身后果。其机制在很大程度上是未知的，但表观遗传学最有可能发挥作用。我们成立了妊娠和儿童表观遗传学（PACE）联盟，并通过使用Illumina 450K BeadChip对13个队列（n = 6685）进行meta分析，分析了怀孕期间母亲吸烟与新生儿血液中超过450,000个CpG位点（CpG）的DNA甲基化之间的关系。在全基因组范围内，超过6000个CpGs与母亲吸烟相关的甲基化差异具有统计学意义（错误发现率为5%），其中包括2,965个CpGs，对应2017个先前与新生儿或成人吸烟和甲基化无关的基因。有几种基因与母亲吸烟（例如，口面部裂和哮喘）或成人吸烟（例如，某些癌症）可能引起的疾病有关。许多差异甲基化的CpGs与基因表达相关。我们观察到对发育至关重要的通路和过程富集。在年龄较大的儿童中（5个队列，n = 3187）， 100%的CpGs至少给出了名义上的显著性水平，远高于偶然预期（p值< 2.2 x 10(-16)）。研究结果对于不同的归一化方法和细胞类型调整都是稳健的。在这项甲基化数据的大规模荟萃分析中，我们发现了许多与母亲在怀孕期间吸烟并持续到儿童后期有关的基因座，并为这种重要暴露的潜在影响机制提供了见解。
Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 x 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.