Pharmacogenomics of Antidepressant Response

描述(由申请人提供)：重度抑郁障碍是一种常见的致残精神疾病，通常使用选择性5-羟色胺再摄取抑制剂抗抑郁药治疗。到目前为止的研究表明，抗抑郁反应与神经递质调节通路和抗抑郁新陈代谢通路中的基因之间存在关联。基于这些观察，这项应用被设计用来在一个史无前例的大小的临床样本中识别抗抑郁药物反应的遗传决定因素，该样本使用单一的抗抑郁药物治疗，其治疗反应已被仔细确定。最终目的是阐明对抗抑郁药物反应的遗传决定因素，作为了解抗抑郁作用机制和开发新的抑郁症治疗药物的重要前提。我们的具体假设是，涉及西酞普兰反应的重要表型部分是由可检测到的遗传因素介导的。我们建议对STAR*D(缓解抑郁的顺序治疗替代疗法)方案期间获得的DNA集合(约1,400个)进行大规模的遗传关联研究，这是一项涉及约4,000名DSM-IV严重抑郁障碍患者的大型多部位治疗研究。我们建议：1)根据先前的生物学或遗传学证据，对该样本进行分型，以确定20个抗抑郁候选基因中的反应表型和变异之间的关联；以及2)在反应表型和大约100,000个基于基因的DNA变异之间进行全基因组关联研究。次要的特殊目标是：1)通过候选基因或全基因组方法确定与反应表型正相关的序列基因，以识别潜在的反应相关等位基因；2)开发精炼的表型和新的假设，以测试与治疗反应结果的关联。功率计算表明，可以检测到表型分组之间的有意义的差异。如果确定了导致这些药物反应或耐受性差异的很大一部分的基因，那么检测DNA变异和抗抑郁药物反应之间的任何联系最终可能会产生重大的临床影响。这些发现可能为我们定义药物治疗的临床有用的遗传预测因子并将其应用于患者群体的能力提供步骤。

DESCRIPTION (provided by applicant): Major Depressive Disorder is a common and disabling psychiatric illness, usually treated with a selective serotonin reuptake inhibitor antidepressant. Studies to date suggest that there are associations between antidepressant response and genes in both neurotransmitter regulatory pathways and antidepressant metabolism pathways. Based on these observations, this application is designed to identify genetic determinants for antidepressant response in a clinical sample of unprecedented size, treated with a single antidepressant, whose treatment response has been carefully ascertained. The ultimate goal is to elucidate genetic determinants of response to antidepressants as an important prerequisite to understanding the mechanism of antidepressant action and development of novel therapeutic agents for depression. Our specific hypothesis is that important phenotypes involving response to citalopram are in part mediated by detectable genetic factors. We propose a large-scale genetic association study on a collection of DNA's (about 1,400) obtained during the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) protocol, a large multi-site treatment study involving about 4,000 persons with DSM-IV Major Depressive Disorder. We propose to: 1) genotype this sample for association between response phenotypes and variants in 20 antidepressant response candidate genes based on prior biological or genetic evidence, and 2) perform a whole genome association study between response phenotypes and about 100,000 gene-based DNA variants. Secondary specific aims are to: 1) sequence genes positively associated with response phenotypes identified using candidate gene or whole genome approaches to identify potential response-related alleles, and 2) develop refined phenotypes and novel hypotheses to test for association to treatment response outcomes. Power calculations suggest meaningful differences between phenotypic groupings can be detected. Detecting any association between DNA variations and antidepressant response could ultimately have a significant clinical impact if a genotype that accounts for a substantial portion of variance in response or tolerability of these medications is identified. These findings could provide steps toward our ability to define clinically useful genetic predictors of pharmacological treatment and apply them to patient populations.