2/6 The Genetics of Endophenotypes and Schizophrenia

描述（由申请方提供）：精神分裂症遗传学联盟（COGS-2）是一项6中心协作关联R 01研究，旨在了解2,000例患者和1,000例社区比较受试者（CCS）中精神分裂症功能重要的定量神经生理学和神经认知内表型的遗传结构以及定性表型。在最初的支持期间，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、采集、质量保证和先证者（N=305）、临床上未受影响的家庭成员（N= 1，014）和CCS（N=505）中这些内表型的分析。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更新将扩展原始3种神经生理学和3种神经认知内表型的使用，以及使用计算机化神经认知组合（CNB）从COGS-1衍生的其他可遗传内表型。鉴于这些内在表型与功能结局的关系越来越重要，COGS-2还将增加一组功能状态评估，包括基于神经元的、替代的和真实世界的功能状态。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将侧重于从通过特定目标1招募的2，000名精神分裂症患者和1，000名CCS的新样本中确定，测试和获得DNA。在特定目标2中，将使用9种COGS-2定量内表型和精神分裂症定性诊断的COGS-2病例对照数据，在遗传疾病研究中心（CIDR）使用当前和最具信息性的平台进行全基因组关联研究（GWAS）。使用CIDR平台中未包含的许多强推断衍生的SNP的互补关联研究将利用COGS SNP芯片阵列（94个候选基因，1536个SNP）来评估与精神分裂症中的内表型缺陷以及精神分裂症本身相关的SNP和拷贝数变异（CNV）。在具体目标3中，将与这些内表型和精神分裂症相关的SNP和CNV与公开可用的数据库（例如，GAIN，CATIE，BROAD）。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，以识别和查询关键的遗传数据，以加强对精神分裂症易感基因的搜索，加强内在表型策略，并最终确定治疗和改善精神分裂症患者功能的分子靶点。 公共卫生相关性：精神分裂症是一种破坏性的大脑疾病，袭击年轻人，并伴随着深刻和毁灭性的疾病负担，通常是患者的一生。精神分裂症遗传学联合会（Consortium on the Genetics of Schizophrenia）（“COGS-2”）题为“内表型和精神分裂症的遗传学”的项目研究了精神分裂症患者中核心神经生理学和神经认知过程中损伤的遗传基础。一旦我们了解了这些异常的遗传结构，就可以开发旨在改善精神分裂症患者功能和生活质量的新药。

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.