Functional Characterization of Risk Variants for Psychotic Illness in the GWAS Er

描述（由申请人提供）：这是NIMH指导研究科学家发展奖（K01）的再提交，题为“GWAS时代精神疾病风险变异的功能特征”。（1 K01 MH086714-01） 2009年2月，行为遗传学和流行病学研究科对其进行了审查，并获得了239分的优先评分。该奖项为候选人实现其长期职业目标提供了一个重要的机会：独立开展转化精神病学遗传学研究，并有助于理解遗传变异如何影响导致精神疾病发展的神经功能。候选人的兴趣是精神病学遗传学，特别侧重于阐明从DNA变异到表征精神疾病的异常脑功能的病因学途径。在奖励期间，研究人员培训的主要重点将是分子遗传学、基因组学和生物信息学，这些领域的研究人员没有接受过正式培训，但对其拟议的调查和过渡为独立研究人员的专业知识的发展至关重要。广泛的实践培训活动将使候选人能够在奖励期结束时独立设计和进行基因实验和分析，并有很高的可能性在未来提交R01研究项目。候选人是哈佛医学院麦克莱恩医院的讲师。她提出的研究项目将在麦克莱恩医院的认知神经科学实验室（主任：Dean Salisbury博士，该申请的顾问）和哈佛医学院的精神病学和神经发育遗传学部门（Jordan Smoller博士，该申请的导师）进行。先前的研究表明，四种神经生理特征（即P300振幅和潜伏期，P50抑制和γ波段反应）是精神病的推定内表型，并捕获了脑功能的三个重要领域。本研究的目的是通过绘制疾病易感性变异对脑功能三个关键区域的影响，利用这些定量内表型来表征全基因组关联研究中发现的疾病易感性变异的神经生理效应。首先，候选人将从精神病患者和对照组中收集DNA样本和神经生理特征数据，为内表型定位提供资源。其次，在行为层面，她将通过对精神分裂症和精神病性双相情感障碍患者伽玛波段反应（GBR）的测量来检查皮质神经网络功能障碍，以进一步阐明这两种疾病中伽玛波段反应的重叠和不同特征。第三，在分子遗传水平上，她将在完成的GWAS分析中选择与双相情感障碍（BPD）、精神分裂症（SCZ）或精神病临床表型相关的最有力证据的风险变异，并检查它们与定量内表型的关联，以解决受这些风险变异影响的特定功能域的关键问题。她还将在大型精神分裂症遗传学联盟（COGS）研究中与精神分裂症相关的内表型显著相关的基因型标记物，以复制SCZ患者中COGS的发现，并将其扩展到检查精神病性双相患者的功能影响。

DESCRIPTION (provided by applicant): This is a resubmission of an NIMH Mentored Research Scientist Development Award (K01) entitled "Functional Characterization of Risk Variants for Psychotic Illness in the GWAS Era." (1 K01 MH086714-01) It was reviewed by the Behavioral Genetics and Epidemiology Study Section in February 2009 and received a priority score of 239. This award offers an important opportunity to prepare the candidate to achieve her long term career goal: to carry out translational psychiatric genetics research independently and to contribute to the understanding of how genetic variations influence on neural functions that contribute to the development of psychotic illnesses. The candidate's interest is in psychiatric genetics, with a particular focus on elucidating the etiologic pathways from DNA variants to the abnormal brain function that characterizes psychotic illness. The primary focus of the investigator's training during the award period will be in molecular genetics, genomics, and bioinformatics, which are areas where the investigator has not had formal training but will be essential to develop expertise for her proposed investigation and for her transition to be an independent investigator. The extensive hands-on training activities will allow the candidate to design and conduct genetic experiments and analyses independently by the end of the award period and have a high likelihood of success for submitting a R01 research project in the future. The candidate is an instructor at McLean Hospital, Harvard Medical School. Her proposed research project will be carried out at the Cognitive Neuroscience Laboratory (Director: Dr. Dean Salisbury, advisor on this application) McLean Hospital and at the Psychiatric and Neurodevelopmental Genetics Unit (Dr. Jordan Smoller, mentor of this application) Harvard Medical School. Previous studies indicate that four neurophysiologic traits (i.e., P300 amplitude and latency, P50 inhibition, and Gamma band response) are putative endophenotypes for psychotic illness and capture three important domains of brain function. The goals of this study are to use these quantitative endophenotypes to characterize the neurophysiological effects of disease susceptibility variants identified by genomewide association studies by mapping their effects on three key domains of brain function. First, the candidate will collect DNA samples and neurophysiological trait data from a sample of patients with psychotic illness and control subjects to provide a resource for endophenotype-mapping. Second, at the behavior level, she will examine cortical neural network dysfunction as measured by gamma-band response (GBR) in schizophrenia and psychotic bipolar patients to further clarify the overlapping and distinct profiles of GBR for these two disorders. Third, at the molecular genetic level, she will select risk variants that have shown the strongest evidence of association with clinical phenotypes of bipolar disorder (BPD), schizophrenia (SCZ), or psychosis, in completed GWAS analyses, and examine their association with quantitative endophenotypes to address key questions about the specific functional domains influenced by these risk variants. She will also genotype markers that have been significantly associated with schizophrenia linked endophenotypes in the large Consortium on the Genetics of Schizophrenia (COGS) study to replicate the findings that emerge from the COGS among SCZ patients and extend them to examine functional effects in psychotic bipolar patients. PUBLIC HEALTH RELEVANCE: The functional mapping of disease-associated variants onto specific domains of brain function may lead to essential biological insights into the mechanisms by which these genes may produce illness. Such information would provide critical tools for the design of treatment interventions aimed at reducing the severity or preventing the onset of psychotic disorder.