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

2/2 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: 10674837
• 负责人: PATRICK F SULLIVAN
• 金额: $ 137.47万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674837
• 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

Project Summary/Abstract 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.

项目概要/摘要 该提案汇集了来自世界各地的研究人员，对重症患者进行基因研究 采用电休克疗法（ECT）治疗重度抑郁症（MDD）。这些人是 是精神科医生见过的病情最严重的人之一，我们预计基因研究将 拥有更大的权力。该提案的驱动目标是确定遗传变异：1) 与严重 MDD 相关并表明哪些患者适合接受 ECT，以及 2) 影响 对 ECT 的反应并预测哪些患者可能从治疗中受益。 MDD 是导致 全球范围内都有残疾，多达三分之一的患者对一线治疗没有反应。搜索到 找到正确的治疗方法可能需要长时间的反复试验和多次治疗 患者继续遭受痛苦，并面临较高的不良后果（包括自杀）风险。 ECT 是治疗一线治疗难以治愈的严重 MDD 的更有效的治疗方法之一。 然而，即使采用 ECT，仍有三分之一到二分之一的患者在急性发作后未能获得缓解。 治疗和认知障碍可能会限制其更广泛的使用。遗传因素很明显 导致 MDD 风险的因素，最近的全基因组关联研究 (GWAS) 已发现 >100 个易感位点。然而，MDD 是一种异质性疾病，大多数病例都存在于 之前的 GWAS 严重程度较低。研究表明，重度/难治性 MDD 是 一种更具遗传性的亚型，强调通过研究关注严重MDD的潜在好处 那些接受ECT治疗的人。此外，有证据表明遗传因素可能影响临床反应 ECT，但这尚未在全基因组范围内以足够的样本量进行研究。为了解决这些 由于局限性，ECT 联盟遗传学（GenECT，PGC MDD 亚组）汇集了 全球 ECT 中心，包括美国国家抑郁症中心网络 (NNDC) 的中心， 进行基因研究，其目的如下：1) 确定、广泛同意、一致 表型和生物样本 25,000 名接受 ECT 治疗的严重 MDD 患者； 2）进行GWAS 针对年龄、性别和血统匹配的对照，以识别导致风险的遗传变异 严重MDD； 3) 在 10,000 个病例的子样本中进行 ECT 临床反应的 GWAS 前瞻性随访数据，以确定与 MDD 测量值变化相关的遗传变异或 认知障碍的发生。该提议将增进我们对遗传的理解 严重 MDD 的病因学，反过来将推动新的、更有效的药物的开发 针对这种繁重且难以治疗的疾病的治疗策略。此外，它还能识别遗传 甚至在开始之前就可以帮助区分哪些患者适合接受 ECT 的因素 治疗。

项目成果

Polygenic Risk Scores Derived From Varying Definitions of Depression and Risk of Depression.

多基因风险评分源自抑郁症和抑郁症风险的不同定义。

• DOI: 10.1001/jamapsychiatry.2021.1988
• 发表时间: 2021-08-11
• 期刊: JAMA psychiatry
• 影响因子: 25.8
• 作者: B. Mitchell;J. Thorp;Yeda Wu;A. Campos;D. Nyholt;S. Gordon;D. Whiteman;C. Olsen;I. Hickie;N. Martin;S. Medl;N. Wray;Enda M. Byrne
• 通讯作者: Enda M. Byrne

The Genomics of Electroconvulsive Therapy International Consortium (GenECT-ic).

电惊厥治疗基因组学国际联盟 (GenECT-ic)。

• 发表时间: 2019
• 作者: Baune, Bernhard T;Soda, Takahiro;Gen;Sullivan, Patrick F;Zandi, Peter
• 通讯作者: Zandi, Peter

mBAT-combo: A more powerful test to detect gene-trait associations from GWAS data.

mBAT-combo：一种更强大的测试，用于从 GWAS 数据中检测基因-性状关联。

• 发表时间: 2023-01-05
• 影响因子: 9.8
• 作者: Li, Ang;Liu, Shouye;Bakshi, Andrew;Jiang, Longda;Chen, Wenhan;Zheng, Zhili;Sullivan, Patrick F;Visscher, Peter M;Wray, Naomi R;Yang, Jian;Zeng, Jian
• 通讯作者: Zeng, Jian