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，识别严重抑郁障碍(MDD)的生物学基础一直是困难的。使用全基因组连锁、候选基因和GWA(与NS&GT；20000名受试者)对MDD进行的遗传学研究在识别符合当代复制标准的风险基因座方面尚未成功。主要教训是，考虑到病因异质性的可能作用，针对MDD等高患病率/低遗传率疾病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，以确定与MDD病因学有关的网络和途径。为了尽量减少异质性，我们将研究产后抑郁症(PPD)，这是一种更同质性的MDD类型。虽然大多数女性在产后的头几天到几周都有轻微的情绪症状(“婴儿忧郁症”)，但这些症状通常会自发消失。相比之下，产后抑郁是一种严重而持久的MDD，是分娩最常见的并发症之一(患病率为15%-20%)，是产妇死亡的主要原因。实际上，孕妇是直截了当地进行识别的，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。产后抑郁的研究应该以多种方式减少异质性(仅限女性，按年龄分组，所有受试者都暴露在相同的生物心理社会事件中)。此外，我们已经转向对生物标记物空间的严格研究，以确定具有潜在临床相关性的PPD的区别特征。DNA甲基化标记之所以吸引人，是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有机体状态的补充数据。最后，神经内分泌激素的综合研究对产后抑郁有明显的意义。我们建议：(1)确定和采样1,000个PPD病例和1,000个欣快感对照，均为自报的非裔美国人；(2)使用无偏见/筛选生物标记物评估对500个PPD病例和500个对照进行发现分析(通过下一代外周血技术进行甲基化组学和转录组学)，最先进的统计分析将识别PPD的多变量生物标记物签名；以及(3)在独立样本中进行符合自由意义的生物标记物的验证分析(500个PPD病例和500个对照)。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显然没有得到充分的研究，PPD在非裔美国女性中的患病率更高，与血统异质性是假阳性信号的主要来源的遗传研究相比，它可以成为生物标记物研究的优势。由于相关的发病率、死亡率和个人/社会成本，MDD是一个首要的公共卫生问题。由于对多种异质性来源的内在控制，研究MDD亚型PPD特别吸引人--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。拟议研究的成功完成将为PPD产生强大且可复制的生物标记物签名。这一新知识将提供对PPD特征的与状态相关的变化的洞察，以及对MDD潜在的与特征相关的脆弱性的洞察(特别是结合Gwas的调查结果)。未来的研究可以评估生物标志物签名是否具有预测性效用，如果是的话，合理的初级预防可能变得可行。 公共卫生相关性：产后抑郁症导致巨大的人类痛苦和社会成本。我们的目标是通过研究患有和不患有产后抑郁症的非裔美国女性的血液，迅速了解更多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.