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: 8641415
• 负责人: Mei-Hua Hall
• 金额: $ 13.65万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641415
• 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 of Mental Disorders; Disease; Disease susceptibility; EP300 gene; Future; Genes; Genetic; Genetic Research; Genetic Variation; Genomics; Genotype; Goals; Hospitals; Individual; Intervention; Investigation; Jordan; Laboratories; Lead; Link; Maps; Measures; 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; risk variant; sensory gating; severe mental illness; 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，名为“ GWAS时代的精神病风险变体功能表征”。 （1 K01 MH086714-01）在2009年2月的行为遗传学和流行病学研究部分进行了审查，并获得了239的优先评分。该奖项为候选人提供了一个重要的机会，可以使候选人能够实现她的长期职业范围：为对概括性的研究促进了对概括性的疾病的发展，以实现对概括性的疾病的发展，以实现对概括性的发展。候选人的兴趣是精神遗传学，特别着重于阐明从DNA变异到表征精神病疾病的异常大脑功能的病因学途径。在奖励期间，研究者培训的主要重点是分子遗传学，基因组学和生物信息学，这是研究人员没有进行正规培训的领域，但对于培养其拟议研究的专业知识以及她的过渡至关重要。广泛的动手培训活动将使候选人能够在奖励期结束前设计和进行遗传实验并独立进行遗传实验，并在未来提交R01研究项目方面取得成功很有可能。 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认知神经科学实验室（主任：该应用程序顾问Dean Salisbury博士）以及麦克莱恩医院以及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）。 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带反应）是用于精神病性疾病的假定内表型，并捕获了三个重要的大脑功能领域。这项研究的目标是使用这些定量的内型型来表征疾病易感性变体的神经生理影响，通过绘制其对脑功能的三个关键领域的影响，通过绘制其对全基因组关联研究确定的。首先，候选人将从患有精神病患者和对照对象的患者样本中收集DNA样本和神经生理特征数据，以提供用于映射映射的资源。其次，在行为水平上，她将检查精神分裂症和精神病性双极患者在γ波段反应（GBR）中测量的皮质神经网络功能障碍，以进一步阐明这两种疾病的GBR的重叠和独特的特征。第三，在分子遗传水平上，她将选择与躁郁症（BPD），精神分裂症（SCZ）或精神病的临床表型相关的最强证据，在完成的GWAS分析中，并检查其与这些特定功能范围内有关这些特定功能型域名影响的关键问题的关联。她还将与精神分裂症相关的基因型标志物在大型联盟中有关精神分裂症遗传学（COGS）研究的大型联盟中关联的基因型，以复制SCZ患者中COGS从COGS中出现的发现，并扩展了它们在精神病患者中的功能效应。 公共卫生相关性：将疾病相关的变体的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产生疾病的机制的基本生物学见解。此类信息将为设计旨在减少严重程度或防止精神病发作的治疗干预措施的设计提供关键工具。

项目成果

Effect of DISC1 on the P300 waveform in psychosis.

DISC1 对精神病中 P300 波形的影响。

• DOI: 10.1093/schbul/sbr101
• 发表时间: 2013
• 期刊: Schizophrenia bulletin
• 影响因子: 6.6
• 作者: Shaikh,Madiha;Hall,Mei-Hua;Schulze,Katja;Dutt,Anirban;Li,Kuang;Williams,Ian;Walshe,Muriel;Constante,Miguel;Broome,Matthew;Picchioni,Marco;Toulopoulou,Timothea;Collier,David;Stahl,Daniel;Rijsdijk,Fruhling;Powell,John;Murray,R
• 通讯作者: Murray,R

The genetic and environmental influences of event-related gamma oscillations on bipolar disorder.

• DOI: 10.1111/j.1399-5618.2011.00925.x
• 发表时间: 2011-05
• 期刊: Bipolar disorders
• 影响因子: 5.4
• 作者: Hall MH;Spencer KM;Schulze K;McDonald C;Kalidindi S;Kravariti E;Kane F;Murray RM;Bramon E;Sham P;Rijsdijk F
• 通讯作者: Rijsdijk F

Role of glia in prefrontal white matter abnormalities in first episode psychosis or mania detected by diffusion tensor spectroscopy.

通过扩散张量光谱检测神经胶质细胞在首发精神病或躁狂症中前额白质异常中的作用。

• DOI: 10.1016/j.schres.2019.05.018
• 发表时间: 2019
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: Lewandowski,KathrynE;Du,Fei;Fan,Xiaoying;Chen,Xi;Huynh,Polly;Öngür,Dost
• 通讯作者: Öngür,Dost

Executive functioning in familial bipolar I disorder patients and their unaffected relatives.

• DOI: 10.1111/j.1399-5618.2011.00901.x
• 发表时间: 2011-03
• 期刊: Bipolar disorders
• 影响因子: 5.4
• 作者: K. Schulze;M. Walshe;D. Ståhl;M. Hall;E. Kravariti;R. Morris;N. Marshall;C. Mcdonald;R. Murray;E. Bramon