A Trans-Nordic Study of Extreme Major Depression

项目总结/摘要 重度抑郁症（MDD）影响着全世界超过3亿人。它是导致残疾的主要因素 和自杀，因此是许多不良生活和健康结果的交叉风险因素。它是可遗传的， 全基因组关联最近提供了信息。然而，几乎所有当前MDD样品都没有富集 在具有最高临床严重性的个体中（即，表型分布的极端尾部），一个关键的 临床预测的弱点。我们建议关注“表型极端MDD”。我们将定义这些 在多年的随访中，在人群规模上经验性地对个体进行研究，以捕获具有显著 更差的MDD临床特征（例如，治疗抵抗，密集的治疗模式，精神病）和穷人 结果（例如，社会功能差、残疾、自杀）。表型极端MDD的病例 导致MDD的全球负担。我们证明我们可以识别这些个体和初步数据 提示这些个体具有更大的MDD风险等位基因遗传负担。我们将讨论一个额外的 通过在独立的队列中进行多个高功率复制层来消除该领域的弱点。我们需要知道 快速判断一个有前途的模型是否可以复制和推广，我们已经为此建立了基础设施。 在目标1中，我们将在瑞典人群的伪样本训练集中凭经验识别“表型极端MDD”。 在独立样本中重复（另一个来自瑞典的数据集和来自丹麦的协调数据集， 挪威），然后推广到来自英国的独立样本（苏格兰一代，英国生物银行），以及 美国（PsycheMERGE）在目标2中，我们将验证经验表型极端MDD定义， Aim 1群体中的基因组数据（即，与其他MDD定义相比， 评估具有极端MDD表型的个体是否携带MDD的更高遗传风险分数）。在目标3中， 我们将为极端MDD开发临床上有用的预测算法：我们能否在第一次介绍时预测谁 会发展成极端的MDD表型吗我们将有特殊的统计能力为所有的目标。 成功地完成这些目标将使我们的变革性、第三预防性意图有效， 临床上有用的预测表型极端MDD的后续发展早期在一个人的 治疗史这是实现部署这些模型的总体转换目标的基础 在全国范围内，以改善病情最严重的MDD患者的健康。

Project Summary/Abstract Major depressive disorder (MDD) affects >300 million people worldwide. It is a leading contributor to disability and suicide, and thus a cross-cutting risk factor for many adverse life and health outcomes. It is heritable, and genome-wide association recently been informative. However, nearly all current MDD samples are not enriched in individuals with the highest clinical severity (i.e., the extreme tail of the phenotype distribution), a critical weakness for clinical prediction. We propose to focus on “phenotype extreme MDD”. We will define these individuals empirically on a population scale over years of follow-up in order to capture individuals with markedly worse MDD clinical features (e.g., treatment-resistance, dense patterns of treatment, psychosis) and poor outcomes (e.g., poor social function, disability, suicide). Cases with phenotype extreme MDD disproportionally contribute to the global burden of MDD. We show that we can identify these individuals and preliminary data suggest these individuals have a greater inherited burden of MDD risk alleles. We will address an additional weakness in the field via multiple, highly powered layers of replication in independent cohorts. We need to know quickly whether a promising model can replicate and generalize, and we have built the infrastructure for this. In Aim 1, we will empirically identify “phenotype extreme MDD” in a training set of ⅓ of the Swedish population with replication in independent samples (the other ⅔ from Sweden and harmonized datasets from Denmark and Norway) and then generalization to independent samples from the UK (Generation Scotland, UK Biobank), and the US (PsycheMERGE). In Aim 2, we will validate the empirical phenotype extreme MDD definition using genomic data in the Aim 1 populations (i.e., pedigree- and SNP-heritability, contrast with other MDD definitions, evaluate whether individuals with phenotype extreme MDD carry higher genetic risk scores for MDD). In Aim 3, we will develop clinically useful prediction algorithms for extreme MDD: can we predict at first presentation who will subsequently develop phenotype extreme MDD? We will have exceptional statistical power for all Aims. Successful completion of these aims will enable our transformative, tertiary-preventive intention of valid and clinically useful prediction of the subsequent development of phenotype extreme MDD early in a person’s treatment history. This is foundational to achieve the overarching translational goal of deploying these models on national scales in order to improve the health of MDD patients who are most severely ill.