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，识别重度抑郁症（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进行的MDD遗传研究（nbb1020,000名受试者）尚未成功识别出符合当代复制标准的风险位点。主要的教训是，考虑到病因异质性的可能作用，遗传方法对于高患病率/低遗传性疾病（如重度抑郁症）可能不是最佳的。我们在这里提出了一种替代策略，以确定与MDD病因有关的网络和途径。为了减少异质性，我们将研究产后抑郁症（PPD），这是一种更同质的重度抑郁症。虽然大多数女性在产后的头几天到几周会有轻微的情绪症状（“产后忧郁”），但这些症状通常会自发消退。相比之下，产后抑郁症是重度抑郁症的一种严重和持续性形式，是分娩最常见的并发症之一（患病率为15-20%），也是孕产妇死亡的主要原因。实际上，孕妇是很容易识别的，因为她们经常与医疗系统接触，并且愿意参与围产期问题的研究。PPD的研究应该从多个方面减少异质性（仅限女性，年龄带，所有受试者暴露于相同的生物心理社会事件）。此外，我们已经转向严格的生物标志物空间研究，以确定PPD的潜在临床相关性的显著特征。DNA甲基化标记很有吸引力，因为甲基化与基因表达直接相关。RNA表达特征为组织甚至生物体的状态提供了补充数据。最后，神经内分泌激素的综合研究对PPD具有明确的重要性。我们建议：(1)确定并抽样1000例PPD病例和1000例健康对照，均为自我报告的非裔美国人；(2)对500名PPD病例和500名对照进行无偏倚/筛选生物标志物评估（通过下一代外周血甲基组学和转录组学），并进行最先进的统计分析，以确定PPD的多变量生物标志物特征；(3)在独立样本（500例PPD病例和500例对照）中对符合自由显著性标准的生物标志物进行验证分析。我们对非裔美国女性的关注是最佳的，因为这一美国少数群体的研究明显不足，非裔美国女性的PPD患病率更高，与血统异质性是假阳性信号的主要来源的遗传研究相反，它可以成为生物标志物研究的优势。由于相关的发病率、死亡率和个人/社会成本，重度抑郁症是一个首要的公共卫生问题。由于多重异质性的内在控制，研究重度抑郁症亚型PPD特别有吸引力-我们建议研究所有暴露于怀孕主要危险因素的育龄妇女。此外，产后抑郁症本身是一个重要的、研究不足的人类健康问题，特别是在非裔美国妇女中。该研究的成功完成将为PPD提供强大且可复制的生物标志物特征。这一新知识将有助于深入了解PPD的状态相关改变特征，以及潜在的MDD的特征相关脆弱性（特别是与GWAS结果相结合）。未来的研究可以评估生物标志物是否具有预测效用，如果是，合理的一级预防可能变得可行。

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.