Identifying Biomarkers for Post-Partum Depression in African-American Women

描述（由申请人提供）：与自闭症、双相情感障碍和精神分裂症的进展相反，辨别重度抑郁症（MDD）的生物学基础一直很困难。使用全基因组连锁、候选基因和GWAS（Ns > 20，000例受试者）进行的MDD遗传学研究尚未成功识别符合当代复制标准的风险基因座。主要的教训是，考虑到病因异质性的可能作用，用于高患病率/低遗传性疾病（如MDD）的遗传方法可能是次优的。我们在这里提出了一种替代策略，以确定网络和途径参与的MDD的病因。为了尽量减少异质性，我们将研究产后抑郁症（PPD），一种更同质的MDD类型。虽然大多数妇女在产后的头几天到几周内会有轻微的情绪症状（“婴儿忧郁症”），但这些症状通常会自行消退。相比之下，PPD是MDD的一种严重和持续形式，是分娩最常见的并发症之一（患病率15-20%），也是孕产妇死亡的主要原因。实际上，孕妇很容易识别，因为她们经常与医疗保健系统接触，并愿意参与围产期问题的研究。PPD研究应通过多种方式降低异质性（仅女性、年龄段、所有受试者暴露于相同的生物心理社会事件）。此外，我们已经转向生物标志物空间的严格研究，以确定具有潜在临床相关性的PPD的显著特征。DNA甲基化标记物很有吸引力，因为甲基化与基因表达直接相关。RNA表达特征增加了关于组织甚至生物体状态的补充数据。最后，神经内分泌激素的综合研究对PPD具有明显的意义。我们建议：（1）确定并采样1,000例PPD病例和1,000例正常胸腺对照，均为自我报告的非裔美国人;（2）使用无偏倚/筛选生物标志物评估对500例PPD病例和500例对照进行发现分析（甲基组学和转录组学通过下一代外周血技术），最先进的统计分析将确定PPD的多变量生物标志物特征;和（3）在独立样品（500个PPD病例和500个对照）中进行符合自由显著性标准的生物标志物的验证测定。我们对非洲裔美国妇女的关注是最佳的，因为这个美国少数群体显然研究不足，PPD在非洲裔美国妇女中的患病率较高，与遗传研究相比，血统异质性是假阳性信号的主要来源，它可以成为生物标志物研究的优势。MDD是一个首要的公共卫生问题，由于相关的发病率，死亡率和个人/社会成本。研究MDD子表PPD特别有吸引力，因为对多种异质性来源的内在控制-我们建议研究所有暴露于妊娠主要风险因素的育龄妇女。此外，产后抑郁症本身是一个重要的和研究不足的人类健康问题，特别是在非洲裔美国妇女。成功完成拟议的研究将产生强大的和可复制的PPD生物标志物签名。这一新的知识将提供对PPD特征的状态相关改变的深入了解，并可能提供对MDD的特征相关脆弱性的深入了解（特别是结合GWAS发现）。未来的研究可以评估生物标志物签名是否具有预测效用，如果是这样，合理的一级预防可能变得可行。 公共卫生相关性：产后抑郁症给人类带来巨大痛苦，并给社会带来巨大损失。我们的目标是通过研究有和没有产后抑郁症的非洲裔美国妇女的血液，迅速了解更多关于产后抑郁症的生物学基础。

DESCRIPTION (provided by applicant): In contrast to progress for autism, bipolar disorder, and schizophrenia, discerning the biological basis of major depressive disorder (MDD) has been difficult. Genetic studies of MDD using genome-wide linkage, candidate gene, and GWAS (with Ns > 20,000 subjects) have not been successful in identifying risk loci that meet contemporary standards for replication. Major lessons are that genetic approaches for higher prevalence/lower heritability diseases like MDD may be suboptimal given the likely role of etiological heterogeneity. We propose here an alternative strategy to identify networks and pathways involved in the etiology of MDD. To minimize heterogeneity, we will study postpartum depression (PPD), a more homogenous type of MDD. Although most women have mild mood symptoms in the first few days to weeks postpartum (the "baby blues"), these symptoms usually resolve spontaneously. In contrast, PPD is a severe and persistent form of MDD that is one of the most frequent complications of childbirth (prevalence 15-20%) and is the leading cause of maternal death. Practically, pregnant women are straight-forward to identify, as they have frequent contact with the healthcare system and are willing to participate in research on perinatal problems. The study of PPD should decrease heterogeneity in multiple ways (females only, age-banded, all subjects exposed to the same biopsychosocial event). Moreover, we have moved to the rigorous study of the biomarker space to identify the distinguishing features of PPD of potential clinical relevance. DNA methylation markers are appealing because methylation is directly related to gene expression. RNA expression signatures add complementary data on the state of a tissue and even of an organism. Finally, the comprehensive study of neuroendocrine hormones is of clear salience for PPD. We propose: (1) to ascertain and sample 1,000 PPD cases and 1,000 euthymic controls, all self-reported African-American; (2) conduct discovery analyses using an unbiased/screening biomarker assessment for 500 PPD cases and 500 controls (methylomics and transcriptomics via next-generation technologies on peripheral blood), and state-of-the-art statistical analyses will identify multivariate biomarker signatures for PPD; and (3) conduct validation assays of biomarkers meeting liberal significance criteria in independent samples (500 PPD cases and 500 controls). Our focus on African American women is optimal as this US minority group is manifestly under-studied, the prevalence of PPD is higher in African-American women, and in contrast to genetic studies where ancestry heterogeneity is a major source of false positive signals, it can be a strength in biomarker studies. MDD is a first-rank public health problem due to the associated morbidity, mortality, and personal/societal costs. Studying the MDD sub-form PPD is particularly appealing due to the inherent control for multiple sources of heterogeneity - we propose to study women of child-bearing years who are all exposed to the major risk factor of pregnancy. Moreover, PPD is itself an important and under-studied human health concern, particularly in African-American women. Successful completion of the proposed research will yield strong and replicable biomarker signatures for PPD. This new knowledge would provide insight into state-related alterations characteristic of PPD and potentially to trait-related vulnerabilities to MDD (particularly in combination with GWAS findings). Future research could evaluate whether a biomarker signature is of predictive utility and, if so, rational primary prevention may become feasible. PUBLIC HEALTH RELEVANCE: Postpartum depression causes enormous human suffering and cost to society. Our goal is rapidly to learn more about the biological basis of postpartum depression by studying the blood of African-American women with and without postpartum depression.