ABSTRACT

Women entering pregnancy with elevated body mass index (BMI) face greater risk of adverse outcomes during pregnancy, delivery, and for their offspring later in life, potentially via epigenetics. If epigenetic programming occurs early during in utero development, the differential marks should be detectable in multiple tissues despite the known unique epigenetic profile in each.

We used early-pregnancy BMI as reflection of maternal metabolic milieu exposure in peri-conception and early-pregnancy period. We analysed DNA methylation in paired cord blood and placenta samples among 437 newborns from Gen3G, a pre-birth prospective cohort of primarily European descent. We measured DNA methylation in both tissues across the genome in >720,000 CpG sites using the Illumina MethylationEPIC array. At each site, we used linear mixed models (LMMs) with an unstructured variance-covariance matrix to test for an association between maternal early-pregnancy BMI and DNA methylation in both tissues (modelled as M-values). We adjusted for tissue-specific covariates, offspring sex, gestational age at delivery, and maternal smoking and age.

Women had a mean (SD) BMI of 25.4 (5.7) kg/m² measured at first trimester visit (mean=9.9 weeks). Early-pregnancy BMI was associated with differential DNA methylation levels in paired-tissue analyses at two sites: cg10593758 (β=0.0126, SE=0.0025; P=4.07e-7), annotated to CRHBP, and cg0762168 (β=−0.0094, SE=0.0018; P=2.78e-7), annotated to CCDC97.

Application of LMMs in DNA methylation data from distinct fetal-origin tissues allowed us to identify CpG sites at which early-pregnancy BMI may have an epigenetic ‘programming’ effect on overall fetus development. One site (CRHBP) may play a role in hypothalamic-pituitary-adrenal axis regulation.

摘要

怀孕期间体重指数 (BMI) 升高的女性在怀孕、分娩和晚年的后代中面临更大的不良后果风险，这可能是通过表观遗传学来实现的。如果表观遗传编程发生在子宫内发育的早期，则应该在多个组织中检测到差异标记，尽管每个组织中都有已知的独特表观遗传特征。

我们使用早期妊娠 BMI 作为围孕期和妊娠早期母体代谢环境暴露的反映。我们分析了来自 Gen3G 的 437 名新生儿的配对脐带血和胎盘样本中的 DNA 甲基化，Gen3G 是一个主要是欧洲血统的出生前前瞻性队列。我们使用Illumina MethylationEPIC阵列测量了超过 720,000 个 CpG 位点的基因组中两种组织的 DNA 甲基化。在每个站点，我们使用具有非结构化方差-协方差矩阵的线性混合模型 (LMM) 来测试母体早孕 BMI 与两种组织中 DNA 甲基化之间的关联（建模为M值）。我们调整了组织特异性协变量、后代性别、分娩胎龄以及母亲吸烟和年龄。

女性在孕早期就诊时测量的平均 (SD) BMI 为 25.4 (5.7) kg/m ²（平均数 = 9.9 周）。早孕 BMI 与两个位点配对组织分析中的差异 DNA 甲基化水平相关：cg10593758 (β=0.0126, SE=0.0025; P =4.07e-7)，注释为CRHBP和 cg0762168 (β=-0.0094, SE=0.0018；P =2.78e-7)，注释为CCDC97。

LMMs 在来自不同胎儿起源组织的 DNA 甲基化数据中的应用使我们能够确定早期妊娠 BMI 可能对整个胎儿发育产生表观遗传“编程”影响的 CpG 位点。一个部位（CRHBP）可能在下丘脑-垂体-肾上腺轴调节中起作用。