Chronic Psychiatric Disorders: Linking Genes to Functional Disability

描述（由申请人提供）：患有精神分裂症或分裂情感性障碍（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，药物管理和基本的自我护理；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）与SZ在精神病症状和某些最近观察到的遗传关联等方面有一些重叠。BPI患者同样会遭受功能和认知障碍，尽管总体上比SZ患者的程度要轻。与NIH和临床研究人员对改善日常功能障碍的日益重视相一致，我们将检查候选基因与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测量（反映现实世界职业成果所需的技能）的关联；2)广泛采用的神经心理学（NP）电池，来自美国国立卫生研究院（NIH）的matrix倡议（改善精神分裂症认知的测量和治疗研究）。后一种NP测量已知与这些基于性能的测量和现实世界的结果有关。UPSA和NP措施将在对已经参加约翰霍普金斯大学基因研究的约1005名德系犹太人受试者（占1256,700名SZ和556名BPI总样本的80%）的随访中进行。依靠这种遗传上相对孤立的种群的一个优势是遗传同质性更强。1005名随访受试者的遗传分析将依赖于UPSA和matrix - np衍生的一个或多个功能容量因子。此外，将根据先前收集的现实世界残疾指标对功能能力因子进行回归，以便从后者推导出预测前者的方程。这些将依次用于为所有1256名受试者创建代理功能能力指数，用于对更大样本进行并行遗传分析。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方面的生物系统的更多理解和研究，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.