Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
School of Psychology, Laval University, Quebec, QC, Canada.
Clin Epigenetics. 2019 Mar 29;11(1):56. doi: 10.1186/s13148-019-0653-x.
Maternal mood disorders and their treatment during pregnancy may have effects on the offspring epigenome. We aim to evaluate associations of maternal prenatal antidepressant use, anxiety, and depression with cord blood DNA methylation across the genome at birth and test for persistence of associations in early and mid-childhood blood DNA.
A discovery phase was conducted in Project Viva, a prospective pre-birth cohort study with external replication in an independent cohort, the Generation R Study. In Project Viva, pregnant women were recruited between 1999 and 2002 in Eastern Massachusetts, USA. In the Generation R Study, pregnant women were recruited between 2002 and 2006 in Rotterdam, the Netherlands. In Project Viva, 479 infants had data on maternal antidepressant use, anxiety, depression, and cord blood DNA methylation, 120 children had DNA methylation measured in early childhood (~ 3 years), and 460 in mid-childhood (~ 7 years). In the Generation R Study, 999 infants had data on maternal antidepressants and cord blood DNA methylation. The prenatal antidepressant prescription was obtained from medical records. At-mid pregnancy, symptoms of anxiety and depression were assessed with the Pregnancy-Related Anxiety Scale and the Edinburgh Postnatal Depression Scale in Project Viva and with the Brief Symptom Inventory in the Generation R Study. Genome-wide DNA methylation was measured using the Infinium HumanMethylation450 BeadChip in both cohorts.
In Project Viva, 2.9% (14/479) pregnant women were prescribed antidepressants, 9.0% (40/445) experienced high pregnancy-related anxiety, and 8.2% (33/402) reported symptoms consistent with depression. Newborns exposed to antidepressants in pregnancy had 7.2% lower DNA methylation (95% CI, - 10.4, - 4.1; P = 1.03 × 10) at cg22159528 located in the gene body of ZNF575, and this association replicated in the Generation R Study (β = - 2.5%; 95% CI - 4.2, - 0.7; P = 0.006). In Project Viva, the association persisted in early (β = - 6.2%; 95% CI - 10.7, - 1.6) but not mid-childhood. We observed cohort-specific associations for maternal anxiety and depression in Project Viva that did not replicate.
The ZNF575 gene is involved in transcriptional regulation but specific functions are largely unknown. Given the widespread use of antidepressants in pregnancy, as well as the effects of exposure to anxiety and depression, implications of potential fetal epigenetic programming by these risk factors and their impacts on development merit further investigation.
孕妇的情绪障碍及其在怀孕期间的治疗可能会对后代的表观基因组产生影响。我们旨在评估产前使用抗抑郁药、焦虑和抑郁与出生时脐带血全基因组 DNA 甲基化的关联，并在儿童早期和中期的血液 DNA 中检测关联的持续性。
在项目 Viva 中进行了发现阶段，这是一项前瞻性的产前队列研究，在独立的队列 Generation R 研究中进行了外部复制。在项目 Viva 中，1999 年至 2002 年期间在美国马萨诸塞州东部招募了孕妇。在 Generation R 研究中，2002 年至 2006 年期间在荷兰鹿特丹招募了孕妇。在项目 Viva 中，479 名婴儿有关于母亲使用抗抑郁药、焦虑、抑郁和脐带血 DNA 甲基化的数据，120 名儿童在儿童早期（约 3 岁）测量了 DNA 甲基化，460 名在儿童中期（约 7 岁）测量了 DNA 甲基化。在 Generation R 研究中，999 名婴儿有关于母亲抗抑郁药和脐带血 DNA 甲基化的数据。产前抗抑郁药处方是从医疗记录中获得的。在妊娠中期，使用妊娠相关焦虑量表和爱丁堡产后抑郁量表评估焦虑症状，使用Brief Symptom Inventory 在 Generation R 研究中评估抑郁症状。在两个队列中均使用 Infinium HumanMethylation450 BeadChip 进行全基因组 DNA 甲基化测量。
在项目 Viva 中，2.9%（14/479）的孕妇服用抗抑郁药，9.0%（40/445）出现高妊娠相关焦虑，8.2%（33/402）报告出现符合抑郁症状。在孕期接触抗抑郁药的新生儿的 DNA 甲基化水平降低了 7.2%（95%CI，-10.4，-4.1；P=1.03×10），位于 ZNF575 基因体中的 cg22159528 处，并且这种关联在 Generation R 研究中得到了复制（β=-2.5%；95%CI，-4.2，-0.7；P=0.006）。在项目 Viva 中，该关联在儿童早期（β=-6.2%；95%CI，-10.7，-1.6）持续存在，但在儿童中期则没有。我们观察到项目 Viva 中与母亲焦虑和抑郁相关的特定队列关联，但没有得到复制。
ZNF575 基因参与转录调控，但具体功能尚不清楚。鉴于抗抑郁药在怀孕期间的广泛使用，以及焦虑和抑郁的影响，这些风险因素对胎儿表观遗传编程的潜在影响及其对发育的影响值得进一步研究。
