Genetics of Parkinsonism in a Special Population of Untreated Schizophrenia

描述（由申请人提供）：该候选人是一名神经学家/精神病学家，在神经生物学方面受过训练，华盛顿大学医学院（WUStL）精神病学和神经病学助理教授，华盛顿大学医学院是世界领先的精神疾病遗传学和流行病学机构。候选人的近期目标是完成流行病学和遗传学硕士学位，以最大限度地利用他目前资助的研究和在Cloninger博士和Goate博士的指导下提供的机会。他的长期目标是将他的研究生涯集中在帕金森病和精神分裂症之间关系的遗传控制研究上。项目。帕金森氏症在新诊断的未经治疗的精神分裂症患者中非常普遍；它的存在预示着更容易产生抗精神病药物引起的副作用，降低治疗依从性和较差的结果。吸烟与帕金森病呈负相关，而黑质高回声性、执行功能和工作记忆缺陷以及气质和性格清单中伤害回避的增加与运动障碍均呈正相关。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。对未经治疗的患者进行研究，可以防止抗精神病药物的作用将噪声引入到这种表型表现中，因此可以将遗传信号与环境噪声（以治疗为代表）隔离开来。我们确定了一个未经治疗的精神分裂症人群，并收集了一个试点样本来研究患者、他们的一级亲属和文化上适当的对照的临床、神经心理学和神经学特征。我们建议扩大样品。利用该奖项的资金，我们将关注先证者及其兄弟姐妹的临床特征，以及对照者及其兄弟姐妹的临床特征，以调查复合内表型的遗传性，包括帕金森病，吸烟，认知缺陷和黑质高回声性。在奖励期结束时，我们将研究Roi应用程序，以研究所提出的表型与数量性状位点（QTL）的关系。所提出的研究的主要相关性在于测试是否神经生物学上定义良好的个体特征集是由基因决定的可能性。因为这些缺陷可能早于精神病的发病，我们相信我们的策略可能为早期发现和早期干预提供工具，可能导致精神分裂症风险受试者的精神病预防。最后，我们预计我们的研究策略可能为研究和解决精神分裂症患者对尼古丁依赖的脆弱性增加提供新的方法。

DESCRIPTION (provided by applicant): The candidate is a neurologist/psychiatrist with training in neurobiology, and an assistant professor of psychiatry and neurology at the Washington University School of Medicine (WUStL), a world leading institution in genetics and epidemiology of psychiatric disorders. The candidate's immediate goal is to complete a master's degree in epidemiology and genetics to maximize opportunities afforded by his currently funded research and under the mentorship of Dr. Cloninger and Dr. Goate. His long term goal is to concentrate his research career on the study of the genetic control of the relationship between parkinsonism and schizophrenia. Project. Parkinsonism is highly prevalent in newly diagnosed -untreated- patients with schizophrenia; its presence predicts greater susceptibility to neuroleptic-induced side effects, reduced treatment compliance and poorer outcome. Smoking has 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. Studying untreated patients prevents the noise introduced into such phenotypic manifestations by 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 of patients, their first degree relatives, and culturally appropriate controls. We propose to expand the sample. With the funds of this 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 of a 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 testing if a neurobiologically well defined set of individual characteristics is genetically determined. Because these deficits possibly 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 ways to study and address the increased vulnerability of schizophrenic patients to nicotine dependence.