Paquette Alison G, Houseman E Andres, Green Benjamin B, Lesseur Corina, Armstrong David A, Lester Barry, Marsit Carmen J
a Department of Pharmacology and Toxicology , Geisel School of Medicine at Dartmouth College , Hanover , NH , USA.
b School of Biological and Population Health Sciences , College of Public Health and Human Sciences, Oregon State University , Corvallis , OR , USA.
Epigenetics. 2016 Aug 2;11(8):603-13. doi: 10.1080/15592294.2016.1195534. Epub 2016 Jul 1.
The placenta regulates the in utero environment and functionally impacts fetal development. Candidate gene studies identified variation in placental DNA methylation is associated with newborn neurologic and behavioral outcomes including movement quality, lethargic behavior, attention, and arousal. We sought to identify novel regions of variable DNA methylation associated with newborn attention, lethargy, quality of movement, and arousal by performing an epigenome-wide association study in 335 infants from a US birth cohort. Methylation status was quantified using the Illumina HumanMethylation450 BeadChip array and associations to newborn outcomes assessed by the NICU Network Neurobehavioral Scales (NNNS) were identified while incorporating established bioinformatics algorithms to control for confounding by cell type composition. Methylation of CpGs within FHIT (cg15970800) and ANKRD11 (cg16710656) demonstrated genome-wide significance (P < 1.8 × 10(-7)) in specific associations with infant attention. CpGs whose differential methylation was associated with all 4 neurobehavioral outcomes were common to 50 genes involved in biological processes relating to cellular adhesion and nervous system development. Comprehensive methylation profiling identified relationships between methylation of FHIT and ANKRD11, which have been previously linked to neurodevelopment and behavioral outcomes in genetic association studies. Subtle changes in DNA methylation of these genes within the placenta may impact normal variation of a newborn's ability to alter and track visual and auditory stimuli. Gene ontology analysis suggested that those genes with variable methylation related to these outcomes are over-represented in biological pathways involved in brain development and placental physiology, supportive of our hypothesis for a key role of the placenta in neurobehavioral outcomes.
胎盘调节子宫内环境，并在功能上影响胎儿发育。候选基因研究表明，胎盘DNA甲基化的变异与新生儿的神经和行为结果相关，包括运动质量、嗜睡行为、注意力和觉醒。我们试图通过对来自美国一个出生队列的335名婴儿进行全表观基因组关联研究，来确定与新生儿注意力、嗜睡、运动质量和觉醒相关的DNA甲基化可变新区域。使用Illumina HumanMethylation450 BeadChip阵列对甲基化状态进行定量，并确定与新生儿结局（通过新生儿重症监护病房网络神经行为量表（NNNS）评估）的关联，同时纳入既定的生物信息学算法以控制细胞类型组成造成的混杂因素。FHIT（cg15970800）和ANKRD11（cg16710656）内的CpG甲基化在与婴儿注意力的特定关联中显示出全基因组显著性（P < 1.8 × 10(-7)）。其差异甲基化与所有4种神经行为结果相关的CpG在涉及细胞黏附和神经系统发育的生物学过程的50个基因中是常见的。全面的甲基化谱分析确定了FHIT和ANKRD11甲基化之间的关系，这在先前的遗传关联研究中已与神经发育和行为结果相关联。胎盘中这些基因的DNA甲基化的细微变化可能会影响新生儿改变和追踪视觉和听觉刺激能力的正常变异。基因本体分析表明，那些甲基化可变与这些结果相关的基因在参与大脑发育和胎盘生理学的生物学途径中过度富集，支持了我们关于胎盘在神经行为结果中起关键作用的假设。
