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

GWAS Er 中精神疾病风险变异的功能特征

• 批准号: 7892862
• 负责人: Mei-Hua Hall
• 金额: $ 13.8万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892862
• 关键词: Achievement; Address; Affect; Architecture; Area; Automobile Driving; Award; Behavior; Behavioral Genetics; Bioinformatics; Biological; Biological Assay; Biological Neural Networks; Bipolar Disorder; Brain; Clinical; Cognitive; Communication; DNA; Data; Development; Diagnostic and Statistical Manual; Disease; Disease susceptibility; EP300 gene; Future; Genes; Genetic; Genetic Research; Genetic Variation; Genomics; Genotype; Goals; Hand; Hospitals; Individual; Intervention; Investigation; Jordan; Laboratories; Lead; Link; Maps; Measures; Mental disorders; Mentored Research Scientist Development Award; Mentors; Molecular Genetics; Multicenter Studies; National Institute of Mental Health; Neurobiology; Neurons; Neurophysiology - biologic function; Pathogenesis; Pathway interactions; Patients; Predisposition; Psychotic Disorders; Relative (related person); Reporting; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Sampling; Schizophrenia; Severities; Study Section; Susceptibility Gene; Syndrome; TNFRSF5 gene; Training; Training Activity; Transcend; Variant; Work; base; career; case control; clinical phenotype; cognitive neuroscience; cost; design; directed attention; disorder control; disorder risk; endophenotype; epidemiology study; follow-up; genetic epidemiology; genetic variant; genome wide association study; information processing; insight; instructor; interest; investigator training; medical schools; network dysfunction; neurophysiology; novel; prevent; psychogenetics; public health relevance; research study; response; sensory gating; success; therapy design; tool; trait

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.

描述（由申请人提供）：这是 NIMH 指导研究科学家发展奖 (K01) 的重新提交，题为“GWAS 时代精神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科于 2009 年 2 月对其进行了审查，并获得了 239 分的优先分数。该奖项为候选人提供了一个重要的机会，帮助他们实现长期职业目标：独立开展转化精神遗传学研究，并有助于了解遗传变异如何影响神经功能，从而促进精神疾病的发展。候选人的兴趣在于精神遗传学，特别关注阐明从 DNA 变异到表征精神疾病的大脑功能异常的病因途径。获奖期间，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尚未接受过正式培训，但对于为她拟议的研究和过渡为独立研究人员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奖励期结束时独立设计、进行基因实验和分析，并且很有可能在未来提交 R01 研究项目。 该候选人是哈佛医学院麦克莱恩医院的讲师。她提议的研究项目将在麦克莱恩医院认知神经科学实验室（主任：Dean Salisbury 博士，本申请的顾问）和哈佛医学院精神病学和神经发育遗传学单位（Jordan Smoller 博士，本申请的导师）进行。 先前的研究表明，四种神经生理学特征（即 P300 振幅和潜伏期、P50 抑制和伽马带反应）是精神病的假定内表型，并涵盖了大脑功能的三个重要领域。本研究的目标是通过绘制全基因组关联研究确定的疾病易感性变异对大脑功能三个关键领域的影响，利用这些定量的内表型来表征疾病易感性变异的神经生理学影响。首先，候选人将从精神病患者和对照受试者样本中收集 DNA 样本和神经生理学特征数据，为内表型作图提供资源。其次，在行为层面，她将通过伽玛带反应（GBR）测量精神分裂症和精神病性双相情感障碍患者的皮质神经网络功能障碍，以进一步阐明这两种疾病的 GBR 重叠和不同特征。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) 或精神病临床表型相关的最强证据的风险变异，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) 研究中对与精神分裂症相关内表型显着相关的标记进行基因分型，以复制 SCZ 患者 COGS 的研究结果，并将其扩展到检查精神病性双相情感障碍患者的功能影响。 公共卫生相关性：将与疾病相关的变异映射到大脑功能的特定领域可能会导致对这些基因可能产生疾病的机制产生重要的生物学见解。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关键工具。