ISGlobal, Institute for Global Health, Barcelona, Spain.
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Transl Psychiatry. 2024 Sep 20;14(1):383. doi: 10.1038/s41398-024-03094-5.
The placenta plays a crucial role in protecting the fetus from environmental harm and supports the development of its brain. In fact, compromised placental function could predispose an individual to neurodevelopmental disorders. Placental epigenetic modifications, including DNA methylation, could be considered a proxy of placental function and thus plausible mediators of the association between intrauterine environmental exposures and genetics, and childhood and adult mental health. Although neurodevelopmental disorders such as autism spectrum disorder have been investigated in relation to placenta DNA methylation, no studies have addressed the association between placenta DNA methylation and child's cognitive functions. Thus, our goal here was to investigate whether the placental DNA methylation profile measured using the Illumina EPIC array is associated with three different cognitive domains (namely verbal score, perceptive performance score, and general cognitive score) assessed by the McCarthy Scales of Children's functions in childhood at age 4. To this end, we conducted epigenome-wide association analyses, including data from 255 mother-child pairs within the INMA project, and performed a follow-up functional analysis to help the interpretation of the findings. After multiple-testing correction, we found that methylation at 4 CpGs (cg1548200, cg02986379, cg00866476, and cg14113931) was significantly associated with the general cognitive score, and 2 distinct differentially methylated regions (DMRs) (including 27 CpGs) were significantly associated with each cognitive dimension. Interestingly, the genes annotated to these CpGs, such as DAB2, CEP76, PSMG2, or MECOM, are involved in placenta, fetal, and brain development. Moreover, functional enrichment analyses of suggestive CpGs (p < 1 × 10) revealed gene sets involved in placenta development, fetus formation, and brain growth. These findings suggest that placental DNA methylation could be a mechanism contributing to the alteration of important pathways in the placenta that have a consequence on the offspring's brain development and cognitive function.
胎盘在保护胎儿免受环境伤害和支持大脑发育方面起着至关重要的作用。事实上，胎盘功能受损可能使个体易患神经发育障碍。胎盘的表观遗传修饰，包括 DNA 甲基化，可以被视为胎盘功能的代表，因此可能是宫内环境暴露与遗传、儿童和成人心理健康之间关联的中介因素。尽管自闭症谱系障碍等神经发育障碍已被研究与胎盘 DNA 甲基化有关，但尚无研究探讨胎盘 DNA 甲基化与儿童认知功能之间的关联。因此，我们的目标是研究使用 Illumina EPIC 阵列测量的胎盘 DNA 甲基化谱是否与 INMA 项目中 255 对母婴的三个不同认知领域（即言语评分、感知表现评分和一般认知评分）相关，这些认知领域是在儿童 4 岁时使用 McCarthy 儿童功能量表评估的。为此，我们进行了全基因组关联分析，包括 INMA 项目中的 255 对母婴数据，并进行了后续的功能分析以帮助解释研究结果。在多重检验校正后，我们发现 4 个 CpG（cg1548200、cg02986379、cg00866476 和 cg14113931）的甲基化与一般认知评分显著相关，2 个不同的差异甲基化区域（DMR，包括 27 个 CpG）与每个认知维度显著相关。有趣的是，注释到这些 CpG 的基因，如 DAB2、CEP76、PSMG2 或 MECOM，参与胎盘、胎儿和大脑发育。此外，对提示性 CpG（p < 1 × 10）进行功能富集分析显示，与胎盘发育、胎儿形成和大脑生长相关的基因集。这些发现表明，胎盘 DNA 甲基化可能是导致胎盘重要通路改变的机制之一，而这些改变对后代的大脑发育和认知功能有影响。
