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

这项建议汇集了来自世界各地的研究人员，对严重的遗传性疾病进行遗传研究。 用电休克疗法（ECT）治疗的重度抑郁症（MDD）。这些人 在精神科医生看到的最严重的疾病患者中，我们预计遗传研究将 拥有更强大的力量该提案的驱动目标是确定1） 与重度MDD相关，并指出哪些患者是ECT的候选人，以及2）影响 并预测哪些患者可能从治疗中受益。MDD是导致 在全球范围内，多达三分之一的患者对一线治疗没有反应。搜索以 找到正确的治疗方法可能需要一个漫长的试验和错误与多种治疗期间， 这些患者继续遭受痛苦，并保持不良后果的高风险，包括自杀。 ECT是一线治疗难治的严重抑郁症的最有效治疗方法之一。 然而，即使使用ECT，也有三分之一到一半的患者在急性发作后未能达到缓解。 治疗和认知障碍可能会出现，限制其更广泛的使用。很明显遗传因素 导致MDD的风险，最近的研究全基因组关联研究（GWAS）已经确定 >100个易感基因座。然而，MDD是一种异质性条件， 既往GWAS的严重程度较低。研究表明，重度/难治性MDD是 一种更易遗传的亚型，通过研究强调了关注重度MDD的潜在益处 接受ECT治疗的患者。此外，有证据表明，遗传因素可能会影响临床反应 ECT，但这还没有研究全基因组足够的样本量。解决这些 限制，ECT联盟的遗传学（GenECT，PGC MDD亚组）已经汇集了 全球的ECT中心，包括美国国家抑郁症中心网络（NNDC）的中心， 进行遗传研究，目的如下：1）确定，广泛同意，一致 表型和生物样本25，000例接受ECT治疗的重度MDD患者; 2）进行GWAS 与年龄、性别和血统相匹配的对照组，以确定导致以下风险的遗传变异： 重度MDD;和3）在10，000例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指标变化相关的遗传变异，或 认知障碍的发生。这一建议将促进我们对遗传学的理解。 严重MDD的病因，这反过来又将促进新的和更有效的开发， 这是一种负担沉重且难以治疗的疾病的治疗策略。此外，它还将识别遗传 可以帮助区分哪些患者是ECT的良好候选人的因素，甚至在开始之前 治疗

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.