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

• 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
• 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

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，药物遗传学一直保持着改善精神病学临床预测的希望， 以个性化治疗作为最终目标。然而，迄今为止，这一承诺仍然存在 由于各种技术和方法论上的局限性，例如：1）有限和 非系统性基因分型，通常涉及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）检查急性的单点 仅响应； 4）小样本量； 5）先前治疗史的异质性。最近的介绍 在快速有效筛选数十万个SNP的新型遗传技术中可能会提供 重新推动了精神病学的药物遗传学/药物基因组学调查的动力；但是，这些 与小样本量相结合的技术增加了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 与精神分裂症患者的几个大型样本的三阶段设计中的关联方法（WGA）方法 在扎克山区医院（ZHH）及其分支机构确定。前两个阶段涉及全基因组 在1600例精神分裂症患者中，筛查> 500,000个SNP，以示例四种关键表型：阳性症状 治疗反应，负面症状，体重和认知功能。该样本的一半（400个高加索人 患者和400名非裔美国人患者）已经在我们的现场和高加索人收集 已经用WGA（Affymetrix 500K微阵列）方法对患者进行了基因分型。我们的WGA工作 日期表明高质量数据产量的可行性（> 97％的呼叫率和> 99.5％的可重复性）和 已发表了一个新型精神分裂症易感性基因座的发现。所有人的全WGA基因分型 将使用1600名患者为这四个患者生成一组基于经验的候选基因 治疗反应表型。然后，将对这些候选基因进行全面检查 在精神分裂症的第一集中，有240名特征良好的患者的密集映射前瞻性地研究了 在受控治疗下一年（第3阶段）。数据分析策略旨在从 最初的宽屏以更异质但非常大的样本，朝向密集的基因分型 详细的结果变量（短期和长期）主要是治疗的人群 精神分裂症第一集中的患者。