1/2 Genetics at an extreme: an efficient genomic study of individuals with clinically severe major depression receiving ECT

1/2 极端遗传学：对接受 ECT 的临床严重抑郁症患者进行有效的基因组研究

• 批准号: 10462540
• 负责人: Peter P. Zandi
• 金额: $ 162.32万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462540
• 关键词: Academic Medical Centers; Acute; Address; Affect; Age; Ally; Automobile Driving; Biological; Brain; Clinical; Clinical Data; Collaborations; Communities; Consent; Data; Demographic Factors; Development; Disease; Disease remission; Electroconvulsive Therapy; Genes; Genetic; Genetic Anticipation; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Hereditary Disease; Heritability; Impaired cognition; Individual; Major Depressive Disorder; Matched Group; Measures; Mental Depression; Mental disorders; Methods; Molecular; Mood Disorders; National Institute of Mental Health; Paper; Pathway interactions; Patient Care; Patients; Persons; Phenotype; Population; Psychiatrist; Psychiatry; Qualifying; Refractory; Research Personnel; Resistance; Risk; Sample Size; Sampling; Severities; Shapes; Signal Transduction; Source; Subgroup; Suicide; Susceptibility Gene; Testing; Work; adverse outcome; brain cell; cell type; cognitive function; cost; disability; effective therapy; follow-up; functional genomics; genetic architecture; genetic predictors; genetic variant; genome wide association study; genome-wide; genome-wide analysis; genomic data; predictive modeling; primary outcome; prospective; psychiatric genomics; response; sex; trait; treatment adherence; treatment strategy; Academic Medical Centers; Acute; Address; Affect; Age; Ally; Automobile Driving; Biological; Brain; Clinical; Clinical Data; Collaborations; Communities; Consent; Data; Demographic Factors; Development; Disease; Disease remission; Electroconvulsive Therapy; Genes; Genetic; Genetic Anticipation; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Hereditary Disease; Heritability; Impaired cognition; Individual; Major Depressive Disorder; Matched Group; Measures; Mental Depression; Mental disorders; Methods; Molecular; Mood Disorders; National Institute of Mental Health; Paper; Pathway interactions; Patient Care; Patients; Persons; Phenotype; Population; Psychiatrist; Psychiatry; Qualifying; Refractory; Research Personnel; Resistance; Risk; Sample Size; Sampling; Severities; Shapes; Signal Transduction; Source; Subgroup; Suicide; Susceptibility Gene; Testing; Work; adverse outcome; brain cell; cell type; cognitive function; cost; disability; effective therapy; follow-up; functional genomics; genetic architecture; genetic predictors; genetic variant; genome wide association study; genome-wide; genome-wide analysis; genomic data; predictive modeling; primary outcome; prospective; psychiatric genomics; response; sex; trait; treatment adherence; treatment strategy

This proposal brings together investigators from around the world to carry out a genetic study of severe major depressive disorder (MDD) treated with electroconvulsive therapy (ECT). These individuals are among the most severely ill people seen by psychiatrists, and we anticipate that genetic studies will have greater power. The driving goals of the proposal are to identify genetic variation that 1) is associated with severe MDD and indicate which patients are candidates for ECT, and 2) influence response to ECT and predict which patients may benefit from treatment. MDD is a leading cause of disability worldwide, and up to a third of patients do not respond to first line therapies. The search to find the right treatment may require a lengthy period of trial and error with multiple treatments during which patients continue to suffer and remain at elevated risk for adverse outcomes, including suicide. ECT is one of the more effective treatments for severe MDD that is refractory to first line therapies. However, even with ECT between one-third to one-half of patients fail to achieve remission after acute treatment, and cognitive impairments may emerge that limit its wider use. It is clear genetic factors contribute to risk for MDD, and recent studies genome-wide association studies (GWAS) have identified >100 susceptibility loci. However, MDD is a heterogeneous condition, and most of the cases in the previous GWAS were of lesser severity. Studies have shown that severe/treatment refractory MDD is a more heritable sub-type, highlighting the potential benefit of focusing on severe MDD by studying those treated with ECT. Moreover, there is evidence that genetic factors may shape clinical response to ECT, but this has not been studied genome-wide with sufficient sample sizes. To address these limitations, the Genetics of ECT Consortium (GenECT, a PGC MDD subgroup) has brought together ECT centers globally, including those in the National Network of Depression Centers (NNDC) in the US, to carry out a genetic study with the following aims: 1) ascertain, broadly consent, consistently phenotype, and biosample 25,000 patients with severe MDD treated by ECT; 2) conduct a GWAS against age, sex and ancestry matched controls to identify genetic variants that contribute to risk for severe MDD; and 3) conduct a GWAS of clinical response to ECT in a sub-sample of 10,000 cases with prospective follow-up data to identify genetic variants associated with changes in measures of MDD or occurrence of cognitive impairments. This proposal will advance our understanding of the genetic etiology of severe MDD which, in turn, will motivate the development of new and more effective treatment strategies for this burdensome and difficult to treat condition. In addition, it will identify genetic factors that can help distinguish which patients are good candidates for ECT even before initiating treatment.

该提案汇集了来自世界各地的调查人员，以进行严重的遗传研究 用电击疗法（ECT）处理的主要抑郁症（MDD）。这些人是 在精神科医生看到的最严重的病人中，我们预计遗传研究将会 有更大的力量。该提案的驱动目标是确定遗传变异，即1） 与严重的MDD相关，并指出哪些患者是ECT的候选者，2）影响 对ECT的反应并预测哪些患者可能受益于治疗。 MDD是主要原因 全世界的残疾人，多达三分之一的患者对第一线疗法没有反应。搜索 找到正确的治疗可能需要长时间的反复试验，并在多种治疗中进行多次治疗 患者继续遭受痛苦，并处于包括自杀在内的不良后果的风险较高。 ECT是对第一线疗法难治性的严重MDD的最有效治疗方法之一。 但是，即使ECT在三分之一到一半的患者之间，急性后也无法缓解 治疗和认知障碍可能会出现，从而限制其更广泛的使用。这是明显的遗传因素 有助于MDD的风险，最近的研究全基因组关联研究（GWAS）已确定 > 100个易感基因座。但是，MDD是一种异质状况，大多数情况 以前的GWA严重程度较小。研究表明，严重/治疗难治性MDD是 一种更可遗传的子类型，强调了通过研究专注于严重MDD的潜在好处 那些用ECT处理的人。此外，有证据表明遗传因素可能会塑造临床反应 为了ECT，但尚未对全基因组进行足够的样本量进行研究。解决这些 局限性，ECT联盟的遗传学（Genect，PGC MDD亚组）已汇总 全球ECT中心，包括美国国家抑郁中心网络（NNDC）的中心， 进行以下目的进行遗传研究：1）确定，广泛的同意，一致地确定 表型和生物样本的25,000例由ECT治疗的严重MDD患者； 2）进行GWAS 针对年龄，性别和祖先匹配对照，以识别有助于风险的遗传变异 严重的MDD; 3）在10,000例子样本中对ECT进行临床反应的GWA 前瞻性随访数据，以识别与MDD度量变化相关的遗传变异或 认知障碍的发生。该提议将提高我们对遗传的理解 严重MDD的病因，反过来会激发新的，更有效的发展 这种繁重且难以治疗状况的治疗策略。另外，它将识别遗传 可以帮助区分哪些患者的因素，即使在启动之前也是ECT的良好候选者 治疗。