Prospective Study of Epigenetic Biomarkers of Postpartum Depression

产后抑郁症表观遗传生物标志物的前瞻性研究

• 批准号: 10679845
• 负责人: Zachary Aaron Kaminsky
• 金额: $ 64.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10679845
• 关键词: Prospective; Study; Epigenetic; Biomarkers; Postpartum

PROJECT SUMMARY This is a proposal to facilitate prospective collection of a sample of women at risk for postpartum depression (PPD) in order to facilitate the validation and refinement of epigenetic biomarkers predictive of the disease. Funds obtained will be used to enable genome-wide genetic and epigenetic analysis of subjects recruited under the BRAINS R01 mechanism. The project will take advantage of the talents of a leader in the field of women's mental health and PPD and a highly experienced DNA methylome researcher. The precipitation of anxiety and depressive symptoms in PPD is thought to be triggered by the rapid withdrawal of gonadal hormones. Evidence out of our laboratory and others implicate a heightened sensitivity of at-risk women to fluctuation in estradiol (E2), specifically on the level of DNA methylation. The central hypothesis that PPD risk may arise due to an altered sensitivity of the epigenetic reprogramming machinery in response to gonadal hormones and that epigenetic markers of PPD resultant from pregnancy related hormonal changes will be detectable in blood. In previous work, we used DNA methylation modeled on hippocampal E2 responsiveness and identified successful epigenetic predictors of human PPD from antenatal blood at the HP1BP3 and TTC9B genes that exhibit >82% accuracy at predicting PPD. In Aim 1, we propose to expand collection of blood and psychological measures from 100 pregnant women with a history of mood disorders and 200 pregnant women from the general population beyond that afforded by the BRAINS R01. Collection will take place within the 1st, 2nd, and within 2 and 6 weeks postpartum in all but 80 women selected for the BRAINS protocol. For all women, we will extend the data collection period by adding a 3 month time point. In Aim 2, genome-wide Illumina HM450 methylation chips will be used to validate existing PPD biomarker efficacy and refine and add to novel biomarker models. In Aim 3, a longitudinal analysis of microarray signatures will be performed and integrated with genetic and hormonal data to understand methylation changes resultant from parturition and potential precipitating PPD episodes. Pyrosequencing will be used to assess promising loci identified in Aims 2 and 3 across all prospective time points. In Aim 4, genome-wide data will be integrated with neuroimaging endophenotypes in the N=80 women who underwent the BRAINS prospective fMRI imaging protocol. Promising loci will be followed up in in vitro cell culture models to assess for causative roles in models of synaptic plasticity. This study will generate an important PPD resource, confirm and expand the utility of early screening, and identify new targets and time points for therapeutic intervention.

项目总结 这是一项促进对有产后抑郁症风险的妇女样本进行前瞻性收集的建议。 (PPD)，以便于验证和完善预测疾病的表观遗传生物标记物。 所获得的资金将用于对招募对象进行全基因组遗传和表观遗传学分析 在大脑R01机制下。该项目将利用一位领域领先者的才能 妇女的心理健康和产后抑郁，以及经验丰富的DNA甲基组研究人员。大气中的降水 产后抑郁的焦虑和抑郁症状被认为是由性腺的快速退出所引发的 荷尔蒙。来自我们实验室和其他实验室的证据表明，高危女性对 雌二醇(E2)的波动，特别是DNA甲基化水平的波动。PPD风险的中心假设 可能是由于表观遗传重编程机制对性腺反应的敏感性改变所致 激素和妊娠相关激素变化所产生的PPD的表观遗传标记将是 在血液中可检测到。在之前的工作中，我们使用了模拟海马区E2反应性的DNA甲基化 并从HP1BP3和TTC9B的产前血液中确定了成功的PPD表观遗传学预测因子 预测产后抑郁的准确率为82%的基因。在目标1中，我们建议扩大血液收集和 100例有情绪障碍史孕妇和200例孕妇的心理测评 来自普通人群，超出了大脑R01的承受能力。收集将在1号内进行， 其次，在产后2周和6周内，除80名女性外，所有女性都被选为Brain方案。为所有人 女性，我们将通过增加3个月的时间点来延长数据收集期限。在AIM 2中，全基因组 Illumina HM450甲基化芯片将用于验证现有PPD生物标记物的有效性，并提炼和添加 到新的生物标志物模型。在目标3中，将对微阵列签名进行纵向分析， 结合遗传和荷尔蒙数据，了解分娩和分娩引起的甲基化变化 潜在的产后抑郁发作。焦磷酸测序将被用来评估在AIMS 2中确定的有希望的基因座 在所有预期时间点上为3。在AIM 4中，全基因组数据将与神经成像相结合 N=80名接受脑部前瞻性功能磁共振成像方案的女性的内表型。 有希望的基因座将在体外细胞培养模型中进行跟踪，以评估在模型中的致病作用 突触可塑性。这项研究将产生一个重要的PPD资源，证实和扩大早期的用途 筛查，并确定新的治疗干预目标和时间点。

项目成果

Antenatal prediction of postpartum depression with blood DNA methylation biomarkers.

• DOI: 10.1038/mp.2013.62
• 发表时间: 2014-05
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Guintivano J;Arad M;Gould TD;Payne JL;Kaminsky ZA
• 通讯作者: Kaminsky ZA

Oxytocin receptor DNA methylation in postpartum depression.

• DOI: 10.1016/j.psyneuen.2016.04.008
• 发表时间: 2016-07
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Kimmel M;Clive M;Gispen F;Guintivano J;Brown T;Cox O;Beckmann MW;Kornhuber J;Fasching PA;Osborne LM;Binder E;Payne JL;Kaminsky Z
• 通讯作者: Kaminsky Z

Biomarker or pathophysiology? The role of DNA methylation in postpartum depression.

生物标志物还是病理生理学？

• DOI: 10.2217/epi.13.51
• 发表时间: 2013
• 期刊: Epigenomics
• 影响因子: 3.8
• 作者: Kimmel,Mary;Kaminsky,Zachary;Payne,JenniferL
• 通讯作者: Payne,JenniferL

Lower allopregnanolone during pregnancy predicts postpartum depression: An exploratory study.

• DOI: 10.1016/j.psyneuen.2017.02.012
• 发表时间: 2017-05
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Osborne LM;Gispen F;Sanyal A;Yenokyan G;Meilman S;Payne JL
• 通讯作者: Payne JL

DNA methylation biomarkers prospectively predict both antenatal and postpartum depression.

• DOI: 10.1016/j.psychres.2019.112711
• 发表时间: 2020-03
• 期刊: Psychiatry research
• 影响因子: 11.3
• 作者: Payne JL;Osborne LM;Cox O;Kelly J;Meilman S;Jones I;Grenier W;Clark K;Ross E;McGinn R;Wadhwa PD;Entringer S;Dunlop AL;Knight AK;Smith AK;Buss C;Kaminsky ZA
• 通讯作者: Kaminsky ZA