5/6 The Genetics of Endophenotypes and Schizophrenia

描述（由申请人提供）：精神分裂症遗传学联盟（COGS-2）是一项6点协作关联R01研究，旨在了解2000名患者和1000名社区比较受试者（CCS）中精神分裂症功能重要的定量神经生理和神经认知内表型和定性表型的遗传结构。在最初的支持期内，COGS-1项目开发了一个强大的研究平台，用于受试者招募、仔细的临床表征、获取、质量保证和分析先证（N=305）、临床未受影响的家庭成员（N=1,014）和CCS （N=505）的这些内表型。此外，COGS-1开发了新的统计遗传学方法，充分利用了迄今为止出现的独特发现。COGS-2的更新将扩展使用原始的3种神经生理和3种神经认知内表型，以及使用计算机化神经认知电池（CNB）从COGS-1衍生的其他遗传内表型。鉴于这些内表型与功能结果的关系日益重要，COGS-2还将增加功能状态评估组，包括基于观察者的、替代的和真实的功能状态。COGS-2将在COGS-1样本中完成最初提出的连锁分析，并使用定制的COGS 1536 SNP芯片从COGS-1数据库中进行候选基因研究。COGS-2将侧重于确定、测试和获取通过Specific Aim 1招募的2000名精神分裂症患者和1000名CCS新样本的DNA。在Specific Aim 2中，一项全基因组关联研究（GWAS）将利用遗传疾病研究中心（CIDR）当前最具信息量的平台，使用9种COGS-2定量内表型的病例对照数据和精神分裂症的定性诊断进行。一项补充关联研究将利用COGS SNP芯片阵列（94个候选基因，1536个SNP），利用CIDR平台中未包含的许多强推断衍生SNP，评估与精神分裂症以及精神分裂症本身的内表型缺陷相关的SNP和拷贝数变异（cnv）。在Specific Aim 3中，与这些内表型和精神分裂症相关的snp和cnv将与公开可用的数据库（例如GAIN， CATIE， BROAD）中的数据进行比较。此外，我们将继续开发COGS平台和相关的创新统计遗传学方法，以识别和询问关键的遗传数据，以加强对精神分裂症易感基因的搜索，增强内表型策略，最终确定治疗和改善精神分裂症患者功能的分子靶点。

DESCRIPTION (provided by applicant): The Consortium on the Genetics of Schizophrenia (COGS-2) is a 6-site collaborative linked R01 study that aims to understand the genetic architecture of functionally important quantitative neurophysiological and neurocognitive endophenotypes and the qualitative phenotype of schizophrenia in 2,000 patients and 1,000 community comparison subjects (CCS). During the initial support period, the COGS-1 project developed a robust research platform for subject recruitment, careful clinical characterization, acquisition, quality assurance, and analysis of these endophenotypes in probands (N=305), clinically unaffected family members (N=1,014) and CCS (N=505). In addition, COGS-1 developed novel statistical genetics methods that take full advantage of the unique findings that have emerged to date. The COGS-2 renewal will extend the use of the original 3 neurophysiological and 3 neurocognitive endophenotypes, as well as additional heritable endophenotypes derived from COGS-1 using the Computerized Neurocognitive Battery (CNB). Given the increased importance of the relationship of these endophenotypes to functional outcome, COGS-2 will also add a functional status assessment battery, consisting of observer-based, surrogate and real-world functional status. COGS-2 will complete the originally proposed linkage analysis in the COGS-1 sample, as well as conduct a candidate gene study from the COGS-1 database using the custom COGS 1536 SNP Chip. COGS-2 will focus on ascertaining, testing and obtaining DNA from new samples of 2,000 schizophrenia patients and 1,000 CCS recruited via Specific Aim 1. In Specific Aim 2, a genome wide association study (GWAS) using the current and most informative platform at the Center for Inherited Disease Research (CIDR) will be performed using the COGS-2 case-control data on the 9 COGS-2 quantitative endophenotypes and the qualitative diagnosis of schizophrenia. A complementary association study, using many strong-inference derived SNPs not included in the CIDR platform, will utilize the COGS SNP Chip array (94 candidate genes, 1536 SNPs) to assess SNP and copy-number variations (CNVs) associated with endophenotype deficits in schizophrenia as well as schizophrenia itself. In Specific Aim 3, SNPs and CNVs associated with these endophenotypes and schizophrenia will be compared with those in publicly available databases (e.g., GAIN, CATIE, BROAD). Furthermore, we will continue to develop the COGS platform and related innovative statistical genetics methods to identify and interrogate crucial genetic data in order to enhance the search for schizophrenia vulnerability genes, enhance the endophenotype strategy and ultimately identify molecular targets for the treatment and improved function of schizophrenia patients. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating brain disorder that strikes young adults and carries with it a profound and devastating disease burden, often for the lifetime of the patient. The Consortium on the Genetics of Schizophrenia ("COGS-2") project entitled, "The Genetics of Endophenotypes and Schizophrenia", examines the genetic basis of impairments in core neurophysiological and neurocognitive processes in schizophrenia patients. Once we understand the genetic architecture of these abnormalities, new medications that aim to improve the functioning and quality of life of schizophrenia patients can be developed.