Chronic Psychiatric Disorders: Linking Genes to Functional Disability

描述(申请人提供)：患有精神分裂症或分裂情感障碍(SZ)的慢性精神障碍患者通常在关键的日常功能技能方面表现出长期残疾，包括社会和职业功能、住宿维护、药物管理和基本自我护理；这些残疾基本上不受当前治疗的影响，与认知功能障碍密切相关。双相I型障碍(BPI)在精神病症状和最近观察到的某些遗传关联方面显示出与SZ的一些重叠。患有BPI的人也同样患有功能和认知障碍，尽管总体上比SZ患者的程度要轻。随着NIH和临床研究人员对改善日常功能残疾的日益重视，我们将检查候选基因，以与1)加州大学圣地亚哥分校(UCSD)基于绩效的技能评估(UPSA)中纳入的最先进的功能能力衡量(反映现实世界职业结果所需的技能)相关；以及2)从NIH Matrics倡议(改善精神分裂症认知的测量和治疗研究)中广泛采用的神经心理学(NP)组合。众所周知，后一种国家利益衡量标准与这些基于绩效的衡量标准和实际结果有关。UPSA和NP将在对约1005名已经参加约翰霍普金斯大学基因研究的德意志裔犹太受试者的后续访问中进行(占1256个样本的80%：700个样本为SZ，556个样本为BPI)。依靠这个基因相对孤立的群体的一个优势是更大的基因同质性。对1005名随访受试者的遗传分析将依赖于来自UPSA和Matrics-NP的一个或多个功能能力因素。此外，功能能力系数(S)将与以前收集的现实世界残疾指标进行回归，以便从后者推导出预测前者的方程(S)。这些将被用来为所有1256名受试者创建一个替代功能能力指数，用于对更大样本的并行遗传分析。我们预计，发现与功能性残疾的遗传关联，独立于更广泛研究的症状领域，如精神病，将导致对影响严重精神障碍这一方面的生物系统的更多了解和研究，并最终在残疾改善方面取得治疗进展。

DESCRIPTION (provided by applicant): Individuals with the chronic mental disorders of schizophrenia or schizoaffective disorder (SZ) often exhibit long-term disability in critical everyday functional skills, including social and occupational functioning, residential maintenance, medication management, and basic self-care; these disabilities are largely unaffected by current treatments and are strongly related to cognitive dysfunction. Bipolar I disorder (BPI) shows some overlap with SZ in, e.g., psychotic symptoms and certain recently observed genetic associations. Individuals with BPI likewise suffer functional and cognitive disabilities, although to a lesser extent on the whole than those with SZ. Consistent with increasing emphasis by NIH and clinical researchers on amelioration of everyday functional disability, we will examine candidate genes for association with 1) state-of-the-art measures of functional capacity (reflecting skills required for real-world occupational outcomes) incorporated in the University of California at San Diego (UCSD) Performance-Based Skills Assessment (UPSA); and 2) the widely-adopted neuropsychological (NP) battery from the NIH MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia). The latter NP measures are known to relate to these performance-based measures and real world outcomes. UPSA and NP measures will be made at follow-up visits to an estimated 1005 Ashkenazi Jewish subjects already participating in Johns Hopkins University genetic studies (80% of total sample of 1256: 700 with SZ and 556 with BPI). An advantage in relying on this relatively-genetically-isolated population is greater genetic homogeneity. Genetic analyses for the 1005 follow-up subjects will rely on one or more functional capacity factors derived from the UPSA and MATRICS-NP. Additionally, the functional capacity factor(s) will be regressed on previously collected indicators of real-world disability in order to derive equation(s) predicting the former from the latter. These will in turn be used to create a proxy functional capacity index for all 1256 subjects, to be used in parallel genetic analyses on the larger sample. We anticipate that uncovering genetic associations with functional disability, independent of more widely studied symptom domains such as psychosis, will lead to increased understanding and research on the biological systems affecting this aspect of severe mental disorders, and eventual therapeutic progress in disability amelioration.