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

描述(由申请人提供)：这是NIMH指导性研究科学家发展奖(K01)的重新提交，该奖项的标题是“GWAS时代精神疾病风险变异的功能表征”(1 K01 MH086714-01)行为遗传学和流行病学研究部门于2009年2月对其进行了审查，并获得了239分的优先分数。这一奖项提供了一个重要的机会，让候选人为实现她的长期职业目标做好准备：独立开展翻译精神病学遗传学研究，并有助于理解基因变异如何影响神经功能，从而促进精神疾病的发展。应聘者感兴趣的是精神病学遗传学，重点是阐明从DNA变异到精神疾病特征的大脑功能异常的致病途径。在获奖期间，调查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，这些领域的调查员没有接受过正式培训，但对于为她提议的调查和向独立调查员过渡发展专业知识至关重要。广泛的实践培训活动将使候选人能够在获奖期结束前独立设计和进行基因实验和分析，并有很高的机会在未来提交R01研究项目。应聘者是哈佛医学院麦克莱恩医院的讲师。她建议的研究项目将在认知神经科学实验室(主任：本申请的顾问迪恩·索尔兹伯里博士)麦克莱恩医院和精神病学和神经发育遗传学部门(乔丹·斯莫勒博士，本申请的导师)哈佛医学院进行。以往的研究表明，P300波幅和潜伏期、P50抑制和Gamma频段反应等四种神经生理学特征可能是精神病的内表型，它们反映了脑功能的三个重要领域。这项研究的目标是使用这些定量的内表型来表征全基因组关联研究确定的疾病易感性变异的神经生理学效应，通过绘制它们在大脑功能的三个关键领域的影响。首先，候选人将从精神病患者和对照受试者的样本中收集DNA样本和神经生理学特征数据，为内表型图谱提供资源。其次，在行为层面，她将检查精神分裂症和精神病双相情感障碍患者的伽马频段反应(GBR)衡量的皮质神经网络功能障碍，以进一步阐明这两种疾病的伽马频段反应(GBR)重叠和不同的特征。第三，在分子遗传学水平上，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)或精神病的临床表型相关的最有力证据的风险变量，并检查它们与定量内表型的关联，以解决有关受这些风险变量影响的特定功能领域的关键问题。她还将在精神分裂症遗传学大型联盟(COGS)的研究中复制SCZ患者的COGS研究中出现的与精神分裂症相关的内表型显著相关的基因标记，并将其扩展到检查精神病双相患者的功能影响。 公共卫生相关性：将与疾病相关的变异功能映射到大脑功能的特定领域，可能会导致对这些基因可能导致疾病的机制的基本生物学见解。这些信息将为设计旨在减轻精神障碍严重程度或预防精神障碍发作的治疗干预措施提供重要工具。

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.