Genetics of Endophenotypes and Schizophrenia

内表型和精神分裂症的遗传学

• 批准号: 7057848
• 负责人: Debby Wen Tsuang
• 金额: $ 45.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057848
• 关键词: adult human (21+); auditory stimulus; clinical research; cooperative study; evoked potentials; family genetics; genetic markers; genetic polymorphism; genetic susceptibility; human subject; interview; linkage mapping; mental disorder diagnosis; neurobiology; neurophysiology; neuropsychological tests; neuropsychology; patient oriented research; performance; phenotype; saccades; schizophrenia; short term memory; startle reaction; verbal learning; visual stimulus

DESCRIPTION (provided by applicant): Neurobiological deficits that serve as informative endophenotype markers have been demonstrated in schizophrenia by a number of different paradigms. Neurophysiological deficits are prominent in P50 event related suppression, prepulse inhibition (PPI) of the startle response, and the antisaccade (AS) task for eye movement dysfunction. Neurocognitive deficits in schizophrenia are revealed by poor performance on the CPT, verbal memory, and tests of working memory. Each of these deficits has also been demonstrated in clinically unaffected relatives of schizophrenia patients, which is evidence that they may reflect part of the heritable risk for the illness. This conclusion is reinforced by findings of deficits in non-psychotic, unmedicated schizophrenia patients, and schizotypal patients. The null hypothesis is that all 6 deficits reflect a single, common underlying heritable dysfunction in all schizophrenia patients. A test of that hypothesis requires measurement of all of these deficits in the same group of schizophrenia patient probands and their relatives. If they are all manifestations of the same genetic dysfunction (although perhaps expressed in different brain areas), then a multivariate analysis would show that they all contribute to a single dimension in both relatives and schizophrenia patients. An alternative hypothesis is that only one or a small subset of deficits is present in each family, which is consistent with the heterogeneity found in current genetic linkage studies. In that case, the multivariate analysis would show the different measures or subsets of them loading onto different dimensions. Schizophrenia itself is likely to be the result of multiple deficits in any individual. Therefore, the analysis is performed in the same cohort of schizophrenia patient probands and their relatives to take advantage of Mendel's second law, which holds that genetically independent deficits segregate independently. Hence, although schizophrenia patient probands themselves have multiple deficits, if the deficits are caused by different genetic factors, then they will segregate to different groups of relatives. This 7 site collaborative RO1 project will gather a combined total of 420 pedigrees (1680 subjects) and 525 normal subjects over 5 years (each site will contribute 1/7th of these totals). Findings of heritable deficits in specific measures will be used to guide the next generation of studies of the genetics of schizophrenia.

描述（由申请人提供）： 许多不同的范式在精神分裂症中证明了作为信息性内表型标记的神经生物学缺陷。在P50事件事件相关的抑制，惊吓反应的预抑制（PPI）和眼动运动功能障碍的任务中，神经生理缺陷是显着的。精神分裂症中的神经认知缺陷显示出在CPT，言语记忆和工作记忆测试的表现不佳。这些缺陷中的每一个也都在精神分裂症患者的临床影响亲属中得到了证明，这证明它们可能反映了可遗传的疾病风险的一部分。通过非精神病，未进行精神分裂症患者和精神分裂症患者的缺陷发现，这一结论得到了加强。无效的假设是，所有6个缺陷都反映了所有精神分裂症患者中一个常见的基本可遗传功能障碍。对该假设的检验需要测量同一组精神分裂症患者概率及其亲戚中的所有这些缺陷。如果它们都是相同遗传功能障碍的表现（尽管可能在不同的大脑区域表达），那么多变量分析将表明它们都会在亲戚和精神分裂症患者中有助于单个维度。另一种假设是，每个家族中只有一个或一小部分缺陷，这与当前遗传链接研究中发现的异质性一致。在这种情况下，多元分析将显示它们的不同度量或子集加载到不同维度上。精神分裂症本身可能是任何个人多次缺陷的结果。因此，该分析是在精神分裂症患者概率及其亲戚中进行的，以利用Mendel的第二定律，该定律认为遗传独立的缺陷会独立隔离。因此，尽管精神分裂症患者概率本身有多种缺陷，但如果缺陷是由不同的遗传因素引起的，那么他们将分离为不同的亲戚群体。这个7个网站协作RO1项目将在5年内共同收集420个谱系（1680名受试者）和525名正常受试者（每个站点将贡献这些总数的1/7）。特定措施中可遗传缺陷的发现将用于指导精神分裂症遗传学的下一代研究。