Department of Obstetrics and Gynecology, Amsterdam UMC, location AMC, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, location AMC, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
Clin Epigenetics. 2019 Feb 4;11(1):18. doi: 10.1186/s13148-019-0616-2.
Children prenatally exposed to maternal depression more often show behavioral and emotional problems compared to unexposed children, possibly through epigenetic alterations. Current evidence is largely based on animal and observational human studies. Therefore, evidence from experimental human studies is needed. In this follow-up of a small randomized controlled trial (RCT), DNA-methylation was compared between children of women who had received cognitive behavioral therapy (CBT) for antenatal depression and children of women who had received treatment as usual (TAU). Originally, 54 women were allocated to CBT or TAU. A beneficial treatment effect was found on women's mood symptoms.
We describe DNA methylation findings in buccal swab DNA of the 3-7-year-old children (CBT(N) = 12, TAU(N) = 11), at a genome-wide level at 770,668 CpG sites and at 729 CpG sites spanning 16 a priori selected candidate genes, including the glucocorticoid receptor (NR3C1). We additionally explored associations with women's baseline depression and anxiety symptoms and offspring DNA methylation, regardless of treatment. Children from the CBT group had overall lower DNA methylation compared to children from the TAU group (mean ∆β = - 0.028, 95% CI - 0.035 to - 0.022). Although 68% of the promoter-associated NR3C1 probes were less methylated in the CBT group, with cg26464411 as top most differentially methylated CpG site (p = 0.038), mean DNA methylation of all NR3C1 promoter-associated probes did not differ significantly between the CBT and TAU groups (mean ∆β = 0.002, 95%CI - 0.010 to 0.011). None of the effects survived correction for multiple testing. There were no differences in mean DNA methylation between the children born to women with more severe depression or anxiety compared to children born to women with mild symptoms of depression or anxiety at baseline (mean ∆β (depression) = 0.0008, 95% CI - 0.007 to 0.008; mean ∆β (anxiety) = 0.0002, 95% CI - 0.004 to 0.005).
We found preliminary evidence of a possible effect of CBT during pregnancy on widespread methylation in children's genomes and a trend toward lower methylation of a CpG site previously shown by others to be linked to depression and child maltreatment. However, none of the effects survived correction for multiple testing and larger studies are warranted.
Trial registration of the original RCT: ACTRN12607000397415 . Registered on 2 August 2007.
与未暴露于抑郁的儿童相比，产前暴露于母亲抑郁的儿童更常出现行为和情绪问题，这可能是通过表观遗传改变造成的。目前的证据主要基于动物和观察性人类研究。因此，需要来自实验性人类研究的证据。在这项对小型随机对照试验（RCT）的随访中，比较了接受认知行为疗法（CBT）治疗产前抑郁的女性的孩子与接受常规治疗（TAU）的女性的孩子之间的 DNA 甲基化情况。最初，54 名女性被分配到 CBT 或 TAU 组。研究发现，CBT 对女性的情绪症状有有益的治疗效果。
我们在全基因组水平上描述了来自 3-7 岁儿童（CBT（N）= 12，TAU（N）= 11）颊拭子 DNA 的 DNA 甲基化发现，在 770,668 个 CpG 位点和 729 个 CpG 位点上，跨越 16 个预先选定的候选基因，包括糖皮质激素受体（NR3C1）。我们还探索了与女性基线抑郁和焦虑症状以及后代 DNA 甲基化的关联，无论治疗情况如何。与 TAU 组相比，CBT 组的儿童总体上 DNA 甲基化水平较低（平均 ∆β= -0.028，95%CI -0.035 至 -0.022）。尽管 CBT 组中与 NR3C1 启动子相关的 68%的探针甲基化程度较低，但以 cg26464411 为最具差异甲基化的 CpG 位点（p= 0.038），但 CBT 和 TAU 组之间 NR3C1 启动子相关探针的平均 DNA 甲基化程度没有显著差异（平均 ∆β= 0.002，95%CI -0.010 至 0.011）。没有一个效应在经过多次测试校正后仍然存在。与基线时患有轻度抑郁或焦虑的女性相比，出生于抑郁或焦虑症状严重的女性的儿童之间的平均 DNA 甲基化没有差异（抑郁的平均 ∆β（抑郁）= 0.0008，95%CI -0.007 至 0.008；焦虑的平均 ∆β（焦虑）= 0.0002，95%CI -0.004 至 0.005）。
我们发现了妊娠期 CBT 可能对儿童基因组中广泛的甲基化产生影响的初步证据，以及先前与抑郁和儿童虐待有关的 CpG 位点的甲基化水平降低的趋势。然而，没有一个效应在经过多次测试校正后仍然存在，需要更大规模的研究。
原始 RCT 的试验注册：ACTRN12607000397415。于 2007 年 8 月 2 日注册。
