Genetics of Parkinsonism in a Special Population of Untreated Schizophrenia

应聘者是一名神经学家/精神病学家，曾接受过神经生物学方面的培训，并是 华盛顿大学医学院的精神病学和神经学，世界领先的 精神疾病遗传学和流行病学研究所。候选人的直接目标是 完成流行病学和遗传学的硕士学位，以最大限度地利用他目前提供的机会 在Cloninger博士和Goate博士的指导下资助了这项研究。他的长期目标是 专注于帕金森病之间关系的基因控制研究 和精神分裂症。项目。帕金森病在新诊断的未经治疗的患者中高度流行 精神分裂症；它的存在预示着对抗精神病药物引起的副作用的易感性增加，减少 治疗依从性和预后较差。吸烟与帕金森症呈负相关，而 黑质的高回声、执行功能和工作记忆障碍，并增加 气质上的伤害回避和性格特征与运动能力呈正相关 减损。这些不同的表型表现与单一的神经生物学机制有关， 即多巴胺能功能下降。研究未经治疗的患者防止噪音进入 这种表型表现是由于抗精神病药物的作用，因此将允许分离 来自环境噪声的遗传信号(以治疗为代表)。我们确定了一个种群 未经治疗的精神分裂症，并收集试点样本以研究临床、神经心理学和 患者、他们的一级亲属的神经学特征，以及文化上合适的对照。我们 建议扩大样本范围。利用这一奖项的资金，我们将专注于临床特征的研究 先证者及其兄弟姐妹以及对照组及其兄弟姐妹的遗传度调查 包括帕金森综合症、吸烟、认知障碍和高回声在内的复合内表型 黑质。在获奖期接近尾声时，我们将研究投资回报申请，以研究 所建议的表型与数量性状基因座(QTL)的关系。《公约》的主要相关性 拟议的研究基于睾丸的可能性，如果神经生物学上定义良好的个体集合 特征是由基因决定的。因为这些缺陷可能早于精神病的发病，所以我们 我相信我们的战略可能提供早期发现和早期干预的工具，可能导致 精神分裂症高危人群精神病的预防。最后，我们预计我们的研究战略 可能为研究和解决精神分裂症患者对尼古丁的易感性增加提供新的方法 依赖。

The candidate is a neurologist/psychiatrist with training in neurobiology, and an assistant professorof psychiatry and neurology at the Washington University School of Medicine (WUStL),a world leading institution in genetics and epidemiology ofpsychiatric disorders. The candidate's immediate goal is to complete a master's degree in epidemiology and genetics to maximizeopportunities afforded by his currently funded research and under the mentorship of Dr. Cloningerand Dr. Goate. His long term goal is to concentrate his research career on the study ofthe genetic control ofthe relationship between parkinsonism and schizophrenia. Project. Parkinsonism is highly prevalent in newlydiagnosed -untreated- patients with schizophrenia; its presence predicts greater susceptibility to neuroleptic-induced side effects, reduced treatment compliance and poorer outcome. Smokinghas a negative association with parkinsonism, whereas hyperechogenicity of the substantia nigra, executive function and working memory deficits, and increased harm avoidance on the temperament and character inventory are all positively associated with motor impairment. These diverse phenotypic manifestations are related to a single neurobiological mechanism, namely decreased dopaminergic function. Studyinguntreated patients prevents the noise introduced into such phenotypic manifestationsby the effects of antipsychotic drugs, and therefore will permit isolation of the genetic signal from environmental noise (represented by treatment). We identified a population with untreated schizophrenia, and collected a pilot sample to study the clinical, neuropsychological and neurological characteristics ofpatients, their first degree relatives, and culturally appropriate controls. We propose to expand the sample. With the funds ofthis award we will focus on the clinical characterization of the probands and their siblings as well as of controls and their siblings to investigate the heritability ofa composite endophenotype including parkinsonism, smoking, cognitive deficit and hyperechogenicity of the substantia nigra. Towards the end of the award period we will work on an Roi application to study the relationship of the proposed phenotype to quantitative trait loci (QTL). The major relevance of the proposed research lies on the possibility of testis if a neurobiologicallywell defined set ofindividual characteristics is genetically determined. Because these deficitspossibly predate the onset of psychosis, we believe our strategy might provide tools for early detection and early intervention, possibly leading to prevention of psychosis in subjects at-risk for schizophrenia. Lastly, we anticipate that our research strategy may indicate new waysto study and address the increased vulnerability of schizophrenic patients to nicotine dependence.