Pharmacogenomics of treatment response in first episode schizophrenia

首发精神分裂症治疗反应的药物基因组学

基本信息

批准号：
7497769
负责人：
Anil K Malhotra
金额：
$ 23.35万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-09 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7497769
关键词：
Acute Adverse effects African American Antipsychotic Agents Arts Candidate Disease Gene Caucasians Caucasoid Race Characteristics Clinical Custom DNA Resequencing Data Data Quality Genetic Genetic Techniques Genome Genotype Goals Haplotypes Heterogeneity Hospitals Inpatients Investigation Literature Maps Measures Medicine Methods Numbers Outcome Outpatients Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Phase Phenotype Population Predisposition Psychiatry Publishing Rate Recording of previous events Recruitment Activity Reproducibility Risperidone Sample Size Sampling Schizophrenia Screening procedure Single Nucleotide Polymorphism Site Staging Structure Symptoms Technology Testing Time Variant Week Weight Weight Gain Work aripiprazole base cognitive change cognitive function cohort cost design first episode schizophrenia genetic variant improved interest novel response

项目摘要

For the last decade, pharmacogenetics has held out the promise of improved clinical prediction in psychiatry, with individualized treatment serving as the ultimate goal. To date, however, that promise has remained unfulfilled due to a variety of technological and methodological limitations, such as: 1) limited and unsystematic genotyping, usually involving a very small number of single nucleotide polymorphisms (SNPs); 2) limited and arbitrarily-defined clinical response phenotypes; 3) examination of an acute, single time-point response only; 4) small sample sizes; and 5) heterogeneity of prior treatment history. The recent introduction of novel genetic techniques to rapidly and efficiently screen hundreds of thousands of SNPs may provide renewed impetus for pharmacogenetic/pharmacogenomic investigations in psychiatry; however, these technologies, combined with small sample sizes, raise the possibility of very large numbers of unreplicated results (false positives). The proposed study is designed to overcome these limitations by applying state-of-the-art whole-genome association (WGA) methods in a three-stage design to several large samples of patients with schizophrenia ascertained at the Zucker Hillside Hospital (ZHH) and its affiliates. The first two stages involve genomewide screening of >500,000 SNPs in 1600 patients with schizophrenia for four key phenotypes: positive symptom treatment response, negative symptoms, weight, and cognitive function. Half of this sample (400 Caucasian patients and 400 African-American patients) has already been collected at our site, and the Caucasian patients have already been genotyped with WGA (Affymetrix 500K microarray) methods. Our WGA work to date has demonstrated feasibility of high-quality data yields (>97% call rates and >99.5% reproducibility) and has resulted in a published finding of a novel schizophrenia susceptibility locus. Full WGA genotyping of all 1600 patients will be utilized to generate an empirically-based set of candidate genes for these four treatment response phenotypes. These candidate genes will then be comprehensively examined with highly dense mapping in 240 well-characterized patients in the first episode of schizophrenia studied prospectively for one year under controlled treatment (Stage 3). The data analytic strategy is designed to "drill down" from an initial broad screen in a more heterogeneous but very large sample, towards the dense genotyping of detailed outcome variables (both short- and longer-term) in a predominantly treatment-naTve population of patients in the first episode of schizophrenia.

在过去的十年中，药物遗传学有望改善精神病学的临床预测，以个体化治疗为最终目标。然而迄今为止，这一承诺仍然存在由于各种技术和方法的限制而未能实现，例如：1）有限和非系统的基因分型，通常涉及极少量的单核苷酸多态性（SNP）； 2) 有限且任意定义的临床反应表型； 3) 急性、单一时间点的检查仅响应； 4）样本量小； 5)既往治疗史的异质性。最近的介绍快速有效地筛选数十万个 SNP 的新型遗传技术可能会提供精神病学药物遗传学/药物基因组学研究的新动力；然而，这些技术与小样本相结合，增加了出现大量未复制的可能性结果（误报）。拟议的研究旨在通过应用最先进的全基因组来克服这些限制对精神分裂症患者的几个大样本进行三阶段设计的关联（WGA）方法在 Zucker Hillside 医院 (ZHH) 及其附属机构确定。前两个阶段涉及全基因组对 1600 名精神分裂症患者中超过 500,000 个 SNP 进行四种关键表型的筛查：阳性症状治疗反应、阴性症状、体重和认知功能。该样本的一半（400 个白人患者和 400 名非洲裔美国患者）已在我们的站点收集，并且白人患者已通过 WGA（Affymetrix 500K 微阵列）方法进行了基因分型。我们的 WGA 工作旨在 date 已证明高质量数据产量的可行性（>97% 的调用率和 >99.5% 的再现性）和已发表了一个新的精神分裂症易感基因座的发现。全部的完整 WGA 基因分型将利用 1600 名患者为这四种疾病生成一组基于经验的候选基因治疗反应表型。然后，这些候选基因将被高度综合地检查。对 240 名精神分裂症首发患者进行的密集绘图进行了前瞻性研究受控治疗一年（第三阶段）。数据分析策略旨在“向下钻取” 在更加异质但非常大的样本中进行初始广泛筛选，以实现密集的基因分型主要未接受过治疗的人群的详细结果变量（短期和长期）精神分裂症首次发作的患者。