Genetic Predictors of Neuropsychological and Functional Outcomes in Schizophrenia

描述(申请人提供)：第二代抗精神病药物已被证明在减少精神分裂症症状方面相当有效，但在改善与受影响个人、其家人和政策制定者相关的行为结果方面进展甚微。精神分裂症功能结局研究的一个主要目标应该是了解旨在提高功能能力的干预措施对谁有效，在什么情况下有效。目前，关于评估或改善功能结果的研究通常主要是在心理社会背景下进行的，而遗传学研究通常被认为在概念上与此类研究相去甚远。然而，很可能对人际交往技能、参与社区活动和工作技能等功能结果有显著的直接和/或间接遗传影响。在这项提案中，我们试图弥合精神分裂症研究光谱中这两个看似遥远的两端。我们之前的非遗传研究表明，认知功能和阴性症状影响功能能力，进而影响精神分裂症的功能结果。另一方面，抑郁症状独立地预测功能结果。我们小组和其他人的单独工作已经证明了许多认知能力和症状的遗传性，并且在识别影响其中一些特征的特定基因方面取得了一些进展。我们现在建议测试这一假设，即几个特定的基因将通过直接途径或通过它们对认知和症状的影响来影响功能结果。为了实现这一目标，我们提出了以下具体目标：1)确定哪些特定的神经心理功能和症状维度可以预测精神分裂症的功能能力和功能结果；2)检测基因多态对现实世界功能的直接和中介影响，特别关注：a)经验支持的候选多态；b)经验支持的候选基因及其周围的所有单倍型标记单核苷酸多态；以及c)本体相关的候选基因；以及3)建立功能结果的多变量模型，方法是：a)评估候选基因之间可能的相加和上位性交互作用；以及b)评估每个候选基因的多效性效应。将基础研究与功能表现研究联系起来，只是未来开发针对异常蛋白的新疗法的第一步，但这是重要的一步。这种疗法的发展可能是一个长期的过程，但最终可能会加强心理社会干预，以改善现实世界的功能。公共卫生相关性：我们将测试几个特定基因对精神分裂症患者的功能结果有贡献的假设，无论是通过直接途径还是通过它们对认知和症状的影响。该项目对个体化治疗和病例管理具有重要意义。通过将基础遗传学研究与功能表现研究联系起来，我们朝着开发针对异常蛋白的新型治疗迈出了第一步，这最终可能会加强心理社会干预，并导致现实世界功能的改善。

DESCRIPTION (provided by applicant): Second-generation antipsychotic medications have proven quite effective in reducing symptoms of schizophrenia, but little progress has been made in improving behavioral outcomes of relevance to affected individuals, their families, and policymakers. A major goal of research on functional outcomes in schizophrenia should be to understand for whom and under what circumstances interventions aimed at improving functional abilities are effective. Currently, research on the assessment or improvement of functional outcomes is usually conducted in a primarily psychosocial context, while genetic studies are typically viewed as conceptually quite distant from such studies. However, it is highly likely that there are significant direct and/or indirect genetic influences on functional outcomes such as interpersonal skills, participation in community activities, and work skills. In this proposal, we seek to bridge these two seemingly distant ends of the spectrum of schizophrenia research. Our previous non-genetic research showed that cognitive functions and negative symptoms influence functional capacity, which in turn influences functional outcomes in schizophrenia. On the other hand, depressive symptoms independently predicted functional outcomes. Separate work by our group and others has demonstrated the heritability of many cognitive abilities and symptoms, and some progress has been made in identifying specific genes that influence some of these traits. We now propose to test the hypothesis that several specific genes will contribute to functional outcomes either through direct pathways or through their influences on cognition and symptoms. To accomplish this goal, we are proposing the following specific aims: 1) To determine which specific neuropsychological functions and symptom dimensions predict functional capacity and functional outcomes in schizophrenia; 2) To detect direct and mediated effects of genetic polymorphisms on real-world functioning, specifically focusing on: a) empirically supported candidate polymorphisms; b) all haplotype-tagging single nucleotide polymorphisms in and around empirically supported candidate genes; and c) ontologically related candidate genes; and 3) To establish multivariate models of functional outcomes, by: a) evaluating possible additive and epistatic interactions between candidate genes; and b) evaluating pleiotropic effects of each candidate gene. Linking basic research with the study of functional performance is only a first step toward future development of novel therapeutics targeted at aberrant proteins, but it is an important one. The development of such treatments is likely to be a long-term process, but one that could ultimately enhance psychosocial interventions to improve real-world functioning. PUBLIC HEALTH RELEVANCE: We will test the hypothesis that several specific genes contribute to functional outcomes, either through direct pathways or through their influences on cognition and symptoms, in schizophrenic patients. This project has important implications for personalized treatment and case management. By linking basic genetic research with the study of functional performance, we take the first step toward the development of new types of treatments targeting aberrant proteins, which could ultimately enhance psychosocial interventions and lead to an improvement in real-world functioning.