Pharmacogenomics of treatment response in first episode schizophrenia

在过去的十年里，药物遗传学为改善精神病学的临床预测提供了希望， 个性化治疗是最终目标。然而，到目前为止，这一承诺仍然存在。 由于各种技术和方法的限制，例如：1）有限， 非系统性基因分型，通常涉及极少数单核苷酸多态性（SNP）; 2)有限的和任意定义的临床反应表型; 3）检查急性单一时间点 仅缓解; 4）小样本量;和5）既往治疗史的异质性。近期出台 新的遗传技术可以快速有效地筛选数十万个SNP， 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，加上小样本量，提高了非常大量的不可复制的可能性， 假阳性（false positive）。 这项拟议的研究旨在通过应用最先进的全基因组技术来克服这些局限性。 关联（WGA）方法在一个三阶段设计的几个大样本的精神分裂症患者 在Zucker希尔赛德医院（ZHH）及其附属机构确定。前两个阶段涉及全基因组 在1600例精神分裂症患者中筛选> 500，000个SNP，以确定四种关键表型：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名白人 患者和400名非洲裔美国患者）已经在我们的研究中心收集， 患者已经用WGA（Affytron 500 K微阵列）方法进行了基因分型。我们的WGA工作是 数据已经证明了高质量数据产出的可行性（>97%调用率和>99.5%再现性）， 导致了一个新的精神分裂症易感基因的发现。所有人的完整WGA基因分型 将利用1600名患者来生成这四个候选基因的基于遗传学的集合。 治疗反应表型。然后，这些候选基因将被全面检查， 对240例首发精神分裂症患者进行了前瞻性研究， 在控制治疗下持续一年（第3阶段）。数据分析策略旨在“深入” 在一个更异质但非常大的样本中进行初步的广泛筛选， 详细的结局变量（短期和长期），主要是初治人群， 精神分裂症的第一次发作。

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.