Chronic Psychiatric Disorders: Linking Genes to Functional Disability

描述（由申请人提供）：患有精神分裂症或情感性精神障碍（SZ）的慢性精神障碍的个体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、住宅维护、药物管理和基本自我护理;这些残疾在很大程度上不受当前治疗的影响，并且与认知功能障碍密切相关。双相I型障碍（BPI）显示出与SZ的一些重叠，例如，精神病症状和某些最近观察到的遗传关联。患有BPI的个体同样遭受功能和认知障碍，尽管总体上比SZ患者的程度要小。与NIH和临床研究人员日益重视改善日常功能障碍相一致，我们将检查候选基因与1）最先进的功能能力测量方法（反映现实世界职业成果所需的技能）纳入加州大学圣地亚哥分校（UCSD）基于绩效的技能评估（UPSA）;以及2）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）电池。后者NP措施是已知的，涉及到这些基于性能的措施和真实的世界的结果。将在随访访视时对已经参加约翰霍普金斯大学遗传研究的约1005名德系犹太受试者进行UPSA和NP测量（占总样本1256的80%：SZ组700人，BPI组556人）。依靠这种相对遗传隔离的群体的一个优势是更大的遗传同质性。1005例随访受试者的遗传分析将依赖于一个或多个来自UPSA和MATRICS-NP的功能能力因子。此外，功能能力系数将根据先前收集的现实残疾指标进行回归，以推导出从后者预测前者的方程式。这些反过来将被用来创建一个代理功能能力指数为所有1256名受试者，用于平行的遗传分析的更大的样本。我们预计，揭示与功能障碍的遗传关联，独立于更广泛研究的症状领域，如精神病，将导致增加对影响严重精神障碍这一方面的生物系统的理解和研究，并最终在改善残疾方面取得治疗进展。

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.