Pharmacogenomics of Mood Stabilizer Response in Bipolar Disorder

描述（由申请人提供）： 情绪稳定剂治疗是双相情感障碍患者药物治疗的核心。然而，对这些药剂的反应在个体之间是高度可变的，这通常导致可能持续数年的药物优化的漫长的试错过程。非常需要更好的反应预测器，以更有效的方式指导医生进行最佳药物治疗。遗传差异可能解释了这种变异性的很大一部分。该项目的目标是确定与情绪稳定剂药物反应相关的遗传变异，这些药物最终可能用作预测性测试。迄今为止，我们小组的研究表明，NTRK 2和PDE 11 A两个基因可以预测锂的反应。在这个项目中，我们提出了一个双管齐下的方法：首先在一个较大的回顾性样本中以探索性的方式寻找基因，然后在一个较小的前瞻性样本中进行复制测试。在回顾性研究中更容易获得更大的样本，然而，前瞻性设计虽然更困难，但提供了更好和更定量的数据。我们的11个研究中心联盟最近完成了一项大型遗传研究的4,500多名双相情感障碍受试者的收集。将从这些既往病例的再联系和招募新的回顾性病例中收集2，000例回顾性受试者。将通过一项8个中心的多中心试验收集960例受试者的前瞻性样本。患者将被招募，筛选和稳定，首先在3个月内接受锂单药治疗。观察1个月后进入维持期，随访2年。主要结局指标是复发时间。锂治疗失败的患者将交叉使用丙戊酸，两种药物均失败的患者将进入常规治疗组。将对回顾性样本进行全基因组关联，并在前瞻性样本中复制阳性SNP。二次分析将包括前瞻性样本的全基因组关联以及与回顾性样本的荟萃分析。这些分析将部分由锂在神经元细胞中的作用机制的研究指导，神经元细胞来源于诱导多能干细胞，而诱导多能干细胞又来源于锂反应者和非反应者的皮肤成纤维细胞。相关性（参见说明）：这个多站点合作项目旨在识别双相情感障碍患者的遗传变异，预测对锂的反应。我们将结合对1600例BP患者锂盐反应的回顾性评估和基因型数据分析，以及对1000例开始锂盐开放试验的BP患者的前瞻性研究。我们的假设是，在几个基因座的遗传变异预测治疗结果与锂。

DESCRIPTION (provided by applicant): Mood stabilizer treatment is central to the pharmacological management of patients with bipolar disorder. However, response to such agents is highly variable between individuals often resulting in a lengthy trial and error process of medication optimization that can last years. There is a great need for a better predictor of response which would guide physicians to the optimum medication in a more efficient fashion. Genetic differences likely explain a substantial portion of this variability. The goal of this project is to identify genetic variants that are associated with response to mood stabilizer medications that might ultimately be useful as a predictive test. Studies to date by our group have implicated two genes, NTRK2 and PDE11A as predicting response to lithium. In this project, we propose a two pronged approach: genes will first be sought in an exploratory fashion in a larger retrospective sample and then tested for replication in a smaller prospective sample. Larger samples are more easily obtainable in a retrospective study, however, prospective designs though more difficult, provide better and more quantitative data. Our 11 site consortium has recently completed collection of over 4,500 bipolar subjects for a large genetic study. 2,000 retrospective subjects will be collected from both recontact of these previous cases and recruitment of new retrospective cases. The prospective sample of 960 subjects will be collected through an eight site multicenter trial. Patients will be recruited, screened and stabilized first on lithium monotherapy over a 3 month period. After one month observation, they will enter the maintenance phase and followed for 2 years. The primary outcome measure will be time to relapse. Patients who fail lithium will be crossed over to valproic acid, those failing both drugs will enter the treatment as usual arm. Genomewide association will be performed on the retrospective sample and positive SNPs replicated in the prospective sample. Secondary analyses will include genomewide association ofthe prospective sample alone and in meta-analysis with the retrospective sample. These analyses will be guided in part by studies of lithium's mechanism of action in neuronal cells derived from induced pluripotent stem cells in turn derived from skin fibroblasts from lithium responders and non-responders. RELEVANCE (See instructions): This multi-site collaborative project aims to identify genetic variants in individuals with bipolar disorder that predict response to lithium. We will do this with a combination of retrospective assessment of lithium response in 1600 individuals with BP disorder and analysis of genotype data, as well as a prospective study of 1000 BP individuals who begin an open trial with lithium. Our hypothesis is that genetic variants at several loci predict treatment outcomes with lithium.