Identifying the genetic causes of depression in a deeply phenotyped population from South Korea

项目概要 该项目旨在满足更好地了解重度抑郁症 (MDD) 病因的需求 作为改善世界主要残疾原因诊断和治疗的一种方法。遗传方法， 识别因果因素并因此寻找新的治疗方法的方法在某些精神科疾病中被证明是成功的 疾病，但由于病情的异质性和MDD的应用带来了挑战 环境因素的重要性。成功需要研究通过评估来考虑异质性 多种临床特征，包括环境风险因素的测量。此外，遗传学研究需要 扩大其覆盖范围以涵盖多个种族不同的人群，以确定其他风险位点， 实现精细绘图和识别可能的因果变异，并扩大多基因预测因子的使用 将疾病传染给更多人群。 NIMH，在发布 PAR-20-026，“精神疾病的遗传结构” “祖先多样化的人口”，认识到这一需求，并响应这一号召，我们建立了一个 韩国和美国调查人员的国际合作，具有良好的记录 东亚大规模精神病学遗传学研究。我们将创建最大的东亚队列 新 MDD 基因的发现，增加基因发现工作的多样性（朝着减少 健康差异），并进行详尽的分析，以确定可能与 MDD 相关的因果变异和基因。 该联盟的目标如下： 目标 1：从韩国收集 DNA 样本和表型 来自 10,000 名患有严重复发性 MDD 的女性和 10,000 名匹配、筛选的对照者。我们将获得一个 一套全面的临床特征和风险因素，一套深层的表型，提供了强大的资源 用于基因鉴定。目标 2：我们将对样本进行基因分型，绘制韩国样本中 MDD 的风险位点，识别 异质性的来源并检查基因和环境如何相互作用导致MDD。目标 3：识别 在东亚人群的荟萃分析中找出 MDD 特有的基因位点，并细化可能的因果变异组 通过在不同种族的群体中使用跨祖先精细绘图。

PROJECT SUMMARY This project addresses the need for a better understanding of the causes of major depressive disorder (MDD) as a way to improve diagnosis and treatment for the world's leading cause of disability. Genetic approaches, a path to identifying causal factors and hence finding novel treatments, are proving successful in some psychiatric disorders, but their application in MDD poses challenges, due to the condition's heterogeneity and the importance of environmental factors. Success requires studies that take into account heterogeneity by assessing multiple clinical features, and include measures of environmental risk factors. Furthermore, genetic studies need to expand their reach to include multiple, ethnically diverse populations, so as to identify additional risk loci, enable fine-mapping and the identification of likely causal variants, and expand the use of polygenic predictors of disease to more populations. NIMH, in issuing PAR-20-026, “Genetic Architecture of Mental Disorders in Ancestrally Diverse Populations”, recognizes this need and in response to this call, we have established an international collaboration of investigators from South Korea and the United States, with a strong track record of large-scale psychiatric genetic research in East Asia. We will create the largest East Asian cohort available for the discovery of new MDD genes, increase the diversity of genetic discovery efforts (a step towards reducing health disparities), and perform exhaustive analyses to identify likely causal variants and genes involved in MDD. The aims of the consortium are as follows: Aim 1: To collect from South Korea DNA samples and phenotypes from 10,000 women with severe recurrent MDD and from 10,000 matched, screened, controls. We will obtain a comprehensive set of clinical features and risk factors, a deep set of phenotypes that provide a powerful resource for gene identification. Aim 2: We will genotype samples, map risk loci for MDD in the Korean sample, identify sources of heterogeneity and examine how genes and environment interact to cause MDD. Aim 3: Identify genetic loci specific for MDD in a meta-analysis of East Asian cohorts, and refine likely sets of causal variants by using trans-ancestry fine-mapping in cohorts of different ethnicities.