The Genetics of Endophenotypes and Schizophrenia

描述（由申请人提供）： 神经生物学缺陷，作为提供信息的内表型标志物已被证明在精神分裂症的一些不同的范例。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）和眼运动功能障碍的反扫视（AS）任务中突出。精神分裂症的神经认知缺陷表现为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在精神分裂症患者的临床未受影响的亲属中得到证实，这表明它们可能反映了疾病的遗传风险。这一结论得到了非精神病性、未用药的精神分裂症患者和精神分裂症患者的缺陷结果的加强。零假设是，所有6个缺陷反映了一个单一的，共同的潜在遗传功能障碍，在所有精神分裂症患者。对这一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），那么多变量分析将显示它们都有助于亲属和精神分裂症患者的单一维度。另一种假设是，只有一个或一个小的子集的缺陷是目前在每个家庭，这是一致的异质性，在目前的遗传连锁研究。在这种情况下，多变量分析将显示加载到不同维度上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，在精神分裂症患者先证者及其亲属的同一队列中进行分析，以利用孟德尔第二定律，该定律认为遗传独立缺陷独立分离。因此，虽然精神分裂症患者先证者本身有多种缺陷，但如果缺陷是由不同的遗传因素引起的，那么他们将被分离到不同的亲属群体。这7个研究中心合作的RO 1项目将在5年内收集总计420个家系（1680名受试者）和525名正常受试者（每个研究中心将贡献这些总数的1/7）。遗传缺陷的具体措施的结果将用于指导下一代精神分裂症的遗传学研究。

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.