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

这项提议汇集了来自世界各地的研究人员，进行了一项严重的遗传病研究 采用电休克疗法(ECT)治疗重度抑郁障碍(MDD)。这些人是 精神病学家看到的病情最严重的人，我们预计基因研究将 拥有更大的力量。这项提案的主要目标是确定1)是 与严重的MDD相关，并指示哪些患者是ECT的候选患者，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 世界各地的残疾患者中，多达三分之一的患者对一线治疗没有反应。搜索目标 找到正确的治疗方法可能需要长时间的反复试验，在此期间进行多次治疗 这些患者继续遭受痛苦，并仍处于包括自杀在内的不良后果的高风险中。 ECT是治疗一线治疗难治的严重MDD的更有效的治疗方法之一。 然而，即使在接受ECT治疗的情况下，也有三分之一到一半的患者在急性发作后未能缓解。 治疗方面，可能会出现认知障碍，限制其更广泛的使用。这是明显的遗传因素 增加MDD的风险，最近的研究发现全基因组关联研究(GWAS)已经确定 &gt；100个易感基因座。然而，MDD是一种异质性疾病，而且 以前的GWA严重程度较轻。研究表明，严重/治疗难治性MDD是 更具遗传性的亚型，通过研究突出关注严重MDD的潜在好处 接受ECT治疗的患者。此外，有证据表明，遗传因素可能影响临床反应。 到ECT，但这还没有在全基因组范围内进行研究，样本量足够大。要解决这些问题 限制，ECT遗传学联合会(GenECT，PGC MDD子组)已将 全球ECT中心，包括美国全国抑郁症中心网络(NNDC)的中心， 进行遗传学研究，目的如下：1)确定、广泛同意、始终如一地 ECT治疗的25,000例重症MDD患者的表型和生物样本；2)进行GWAS 对照年龄、性别和血统的配对对照，以确定导致癌症风险的基因变异 严重的MDD；以及3)对10,000名患有严重MDD的患者进行ECT临床反应的GWA评估 确定与MDD或MDD指标变化相关的遗传变异的前瞻性随访数据 认知障碍的发生。这一提议将促进我们对基因的理解 严重MDD的病因学，这反过来将推动新的和更有效的开发 针对这种繁重和难以治疗的疾病的治疗策略。此外，它还将识别基因 可以帮助区分哪些患者在开始接受ECT之前就适合接受ECT的因素 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.