Genetic Polymorphism of a Schizophrenia Endophenotype

精神分裂症内表型的遗传多态性

• 批准号: 7093928
• 负责人: IKWUNGA WONODI
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093928
• 关键词: clinical research; cognition; disease /disorder etiology; dopamine receptor; executive function; family genetics; genetic polymorphism; genetic susceptibility; genotype; human subject; intelligence; memory; neuropsychological tests; neuropsychology; pathologic process; patient oriented research; performance; prefrontal lobe /cortex; saccades; schizophrenia

DESCRIPTION (provided by applicant): Schizophrenia is a complex disorder with a heritability of around 80%. Identifying disease-related genetic factors has been a major focus of schizophrenia research in recent years. Efforts have been multifaceted with the ultimate goal being to describe a causal path from specific genetic variants, to CNS protein changes, to changes in neuronal functioning, to behavioral effects associated with specific functional impairments. Past efforts to elucidate this causal path have been frustrated by the apparent heterogeneity of the syndrome, which may explain repeated failures to replicate identified disease loci. The schizophrenia diagnosis likely reflects a heterogeneous combination of several such causal paths, and is therefore characterized by a varying collection of phenotypes each associated with specific neurocognitive deficits reflecting the effects of a small subset of genes (or single gene) which act in conjunction with epigenetic processes and environmental factors. Traditional genetic approaches that focus on the presence or absence of the syndromal clinical phenotype, or its symptom domains have generally been less informative than approaches that focus more on disease-related phenotypes. In light of these complexities there is a critical need for alternative phenotypes that reflect specific aspects of disease risk. The catechol-O-methyl transferase (COMT) gene has been implicated in the pathophysiology of schizophrenia by its unique effect on prefrontal dopamine transmission. Frontal cortical neurons play an important role in the modulation of predictive SPEM. Our laboratory has refined several neurophysiological measures that reflect more specific aspects of neuronal functioning (e.g., the development and validation of predictive pursuit gain [PPG] of SPEM). We have applied PPG in an association study with COMT genotype with preliminary data showing a COMT by diagnosis interaction. We selected SPEM because it is an accepted schizophrenia endophenotype with a similar construct to working memory (WM). Our preliminary data suggests a paradoxical effect of COMT genotype on PPG in schizophrenia but not in normal subjects. In the current application, we aim to replicate our SPEM/COMT findings in a larger sample. We will also test the hypothesis that Met/Met COMT, and T/T DAT1 genotypes will result in decreased PPG performance in schizophrenia. In an exploratory framework, we will examine variations in other candidate dopamine genes, the dopamine 2 receptor (DRD2) and the dopamine .3 receptor (DRD3) genes. We will examine the effects of these genes on executive cognition (WCST), WM using Wechsler Adult Intelligence Scale Letter-Number-Sequencing subtest (WAIS-III L-N-S), and visuospatial WM (memory guided saccade). Deciphering the genetic mechanisms of prefrontal dopamine dysfunction in schizophrenia would advance our understanding of the pathophysiology of schizophrenia and may help identify novel treatments.

描述(申请人提供)：精神分裂症是一种遗传率约为80%的复杂疾病。识别与疾病相关的遗传因素是近年来精神分裂症研究的主要焦点。这方面的努力是多方面的，最终目标是描述从特定遗传变异到中枢神经系统蛋白质变化、神经功能变化到与特定功能障碍相关的行为影响的因果路径。过去阐明这一因果路径的努力因该综合征的明显异质性而受挫，这可能解释了重复复制已识别的疾病位点的反复失败。精神分裂症的诊断可能反映了几种这样的因果路径的不同组合，因此其特征是不同的表型集合，每一种表型都与特定的神经认知缺陷有关，反映了与表观遗传过程和环境因素共同作用的一小部分基因(或单个基因)的影响。与更多地关注疾病相关表型的方法相比，关注综合征临床表型或其症状领域的存在或不存在的传统遗传学方法通常提供的信息较少。鉴于这些复杂性，迫切需要能够反映疾病风险特定方面的替代表型。儿茶酚-O-甲基转移酶(COMT)基因在前额叶多巴胺传递中具有独特的作用，在精神分裂症的病理生理学中起重要作用。额叶皮质神经元在预测SPEM的调制中起着重要作用。我们的实验室改进了几个神经生理学指标，以反映神经元功能的更具体方面(例如，SPEM的预测性追踪增益[PPG]的开发和验证)。我们已经将PPG应用于与COMT基因相关的研究中，初步数据显示通过诊断交互作用显示了COMT。我们选择SPEM是因为它是一种被接受的精神分裂症内表型，其结构类似于工作记忆(WM)。我们的初步数据表明，COMT基因对精神分裂症患者PPG的影响是自相矛盾的，但在正常受试者中没有。在目前的应用中，我们的目标是在更大的样本中复制我们的SPEM/COMT发现。我们还将检验Met/Met COMT和T/T DAT1基因型会导致精神分裂症患者PPG表现下降的假设。在一个探索性的框架中，我们将检查其他候选多巴胺基因的变异，即多巴胺2受体(DRD2)和多巴胺3受体(DRD3)基因。我们将检验这些基因对执行认知的影响，使用韦氏成人智力量表字母数字排序分测验(WAIS-III L-N-S)和视觉空间WM(记忆引导的眼跳)。破译精神分裂症前额叶多巴胺功能障碍的遗传机制将促进我们对精神分裂症的病理生理学的理解，并可能有助于寻找新的治疗方法。