Genetics of Endophenotypes and Schizophrenia

内表型和精神分裂症的遗传学

• 批准号: 6574894
• 负责人: Debby Wen Tsuang
• 金额: $ 48.08万
• 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/6574894
• 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）： 作为信息性内表型标记的神经生物学缺陷已通过许多不同的范式在精神分裂症中得到证实。神经生理学缺陷在 P50 事件相关抑制、惊吓反应的前脉冲抑制 (PPI) 以及眼动功能障碍的反扫视 (AS) 任务中表现突出。精神分裂症的神经认知缺陷通过 CPT、言语记忆和工作记忆测试的表现不佳来揭示。这些缺陷中的每一个也在临床上未受影响的精神分裂症患者亲属中得到证实，这证明它们可能反映了该疾病的部分遗传风险。在非精神病、未接受药物治疗的精神分裂症患者和精神分裂症患者中发现的缺陷强化了这一结论。零假设是，所有 6 种缺陷都反映了所有精神分裂症患者中单一的、常见的潜在遗传性功能障碍。对该假设的检验需要测量同一组精神分裂症患者先证者及其亲属的所有这些缺陷。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对亲属和精神分裂症患者的单一维度有贡献。另一种假设是，每个家族中仅存在一个或一小部分缺陷，这与当前遗传连锁研究中发现的异质性一致。在这种情况下，多变量分析将显示加载到不同维度的不同度量或它们的子集。精神分裂症本身很可能是任何个体多重缺陷的结果。因此，分析是在同一组精神分裂症患者先证者及其亲属中进行的，以利用孟德尔第二定律，该定律认为遗传独立的缺陷是独立分离的。因此，尽管精神分裂症患者先证者本身存在多种缺陷，但如果这些缺陷是由不同的遗传因素引起的，那么他们就会被隔离到不同的亲属群体中。这个7个站点合作的RO1项目将在5年内收集总共420个谱系（1680个受试者）和525个正常受试者（每个站点将贡献总数的1/7）。具体措施中遗传缺陷的发现将用于指导下一代精神分裂症遗传学研究。