Genetic Polymorphism of a Schizophrenia Endophenotype

描述（由申请人提供）：精神分裂症是一种复杂的疾病，遗传率约为80%。识别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。研究的努力是多方面的，最终目标是描述一条因果路径，从特定的基因变异到中枢神经系统蛋白的改变，到神经元功能的改变，再到与特定功能障碍相关的行为影响。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，这可能解释了重复已确定疾病位点的失败。精神分裂症的诊断可能反映了几个这样的因果路径的异质组合，因此以不同的表型集合为特征，每种表型都与特定的神经认知缺陷相关，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。传统的遗传学方法侧重于是否存在综合征临床表型，或其症状域，通常比侧重于疾病相关表型的方法提供的信息要少。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）基因通过其对前额叶多巴胺传递的独特作用而与精神分裂症的病理生理有关。额叶皮质神经元在预测性SPEM的调节中起重要作用。我们的实验室已经改进了几种反映神经元功能更具体方面的神经生理学测量（例如，SPEM的预测追踪增益[PPG]的开发和验证）。我们已经应用PPG与COMT基因型的关联研究，初步数据显示COMT的诊断相互作用。我们选择SPEM是因为它是一种公认的精神分裂症内表型，与工作记忆（WM）具有相似的结构。我们的初步数据表明，COMT基因型对精神分裂症患者的PPG有矛盾的影响，而对正常人没有影响。在当前的应用程序中，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基因型是否会导致精神分裂症患者PPG表现下降的假设。在探索性框架中，我们将研究其他候选多巴胺基因，多巴胺2受体（DRD2）和多巴胺的变化。3受体（DRD3）基因。我们将研究这些基因对执行认知（WCST）、WM(使用韦氏成人智力量表字母-数字排序子测试（WAIS-III L-N-S）和视觉空间WM（记忆引导扫视）的影响。破译精神分裂症中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病理生理学的理解，并可能有助于确定新的治疗方法。

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.