Genetic Predictors of Neuropsychological and Functional Outcomes in Schizophrenia

精神分裂症神经心理和功能结果的遗传预测因子

• 批准号: 8301790
• 负责人: MING T. TSUANG
• 金额: $ 59.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301790
• 关键词: Activities of Daily Living; Address; Affect; Antipsychotic Agents; Basic Science; Behavioral; Biological; Biological Models; Candidate Disease Gene; Case Management; Cognition; Cognitive; Communities; DNA Repository; Data; Delusions; Development; Dimensions; Disease model; Distant; Family; Funding; Future; Gene Combinations; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genome; Genotype; Goals; Hallucinations; Haplotypes; Health; Heritability; Heterogeneity; Impaired cognition; Individual; Intervention; Knowledge; Lead; Link; Measures; Mediating; Methods; Minisatellite Repeats; Modeling; Molecular; Molecular Profiling; Multivariate Analysis; Neurobehavioral Manifestations; Ontology; Outcome; Outcome Measure; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Probability; Process; Proteins; Quantitative Trait Loci; RNA; Research; Residual state; Role; Sampling; Scanning; Schizophrenia; Single Nucleotide Polymorphism; Societies; Source; Specificity; Symptoms; Technology; Testing; Time; Validation; Variant; Wages; Work; base; cognitive function; cost; depressive symptoms; endophenotype; functional disability; functional outcomes; gene interaction; genome wide association study; genome-wide; high risk; improved; infancy; insertion/deletion mutation; interest; neuropsychological; new therapeutic target; non-genetic; novel strategies; pleiotropism; prevent; psychosocial; skills; sound; stem; theories; trait

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.

描述（由申请人提供）：事实证明，第二代抗精神病药物已在减少精神分裂症的症状方面非常有效，但是在改善与受影响的个人，家庭和政策制定者的行为结果方面取得了很少的进展。精神分裂症功能结果研究的主要目标应该是了解旨在提高功能能力的干预措施是有效的。当前，有关功能结果评估或改善的研究通常是在主要的社会心理环境中进行的，而遗传研究通常被视为与此类研究相距甚远。但是，很有可能会对诸如人际交往能力，参与社区活动和工作技能等功能结果的直接和/或间接遗传影响。在这一提议中，我们试图弥合精神分裂症研究范围的这两个看似遥远的末端。我们以前的非遗传研究表明，认知功能和负症状会影响功能能力，这反过来又影响了精神分裂症的功能结果。另一方面，抑郁症状独立预测功能结果。我们小组和其他人的单独工作表明了许多认知能力和症状的遗传力，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。现在，我们建议检验以下假设：几个特定基因将通过直接途径或通过对认知和症状的影响来促进功能结果。为了实现这一目标，我们提出以下特定目的：1）确定哪些特定的神经心理学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）检测遗传多态性对现实世界功能的直接和中介作用，特别是：a）经验支持的候选多态性； b）所有在经验支持的候选基因中及其周围的单倍型单核苷酸多态性； c）与本体论相关的候选基因； 3）建立功能结果的多元模型，通过：a）评估候选基因之间可能的添加剂和上皮相互作用； b）评估每个候选基因的多效性作用。将基础研究与功能性能的研究联系起来只是针对异常蛋白质的新型治疗剂的未来发展的第一步，但这是重要的。这种治疗的发展可能是一个长期的过程，但是最终可以增强心理心理干预措施以改善现实世界的功能。