Genetic and Neuropsychological Heterogeneity in Alzheimer's Disease

阿尔茨海默病的遗传和神经心理学异质性

• 批准号: 9098564
• 负责人: Jesse Benjamin Mez
• 金额: $ 12.92万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098564
• 关键词: Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; American; Architecture; Area; Boston; Clinical; Code; Communities; Data; Data Set; Dementia; Disease; Doctor of Medicine; Drug Targeting; Education; Environment; Environmental Risk Factor; Functional disorder; Funding; Future; Genes; Genetic; Genetic Epistasis; Genetic Risk; Genetic Techniques; Genomics; Genotype; Goals; Grant; Head; Health; Heritability; Heterogeneity; Hypertension; Impairment; Incidence; Interdisciplinary Study; International; Joints; Knowledge; Language; Lead; Measures; Medical; Medicine; Memory; Memory impairment; Mentors; Meta-Analysis; Methods; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Parents; Participant; Patients; Phenotype; Positioning Attribute; Process; Psyche structure; Psychometrics; Research; Research Personnel; Risk Factors; Speed; Staging; Training; Universities; Variant; Washington; Work; base; design; drug development; executive function; exome sequencing; gene environment interaction; genetic risk factor; genetic variant; genome wide association study; genome-wide; hands-on learning; insight; member; multidisciplinary; neuroimaging; neuropsychological; profiles in patients; response; skills; theories

DESCRIPTION (provided by applicant): The overarching goal of this application is to provide Dr. Jesse Mez, M.D., M.S. with additional training in the field of Alzheimer's disease (AD) genetics so that he may develop into an independent investigator and skilled future leader of a multidisciplinary research team. Dr. Mez, his mentors and the consultants on the application have designed a research plan and complementary training plan that will engage him in several new areas of study and provide him with the skills necessary for leading a research team with diverse expertise. Patients with AD can present with substantial variation in clinical presentation While a considerable number of genetic risk factors have been identified for the incidence of AD, few genetic risk factors have been identified for the variation in clinical presentation of AD. Genetic risk factors provide insight into underlying AD pathophysiology and offer potential targets for disease-modifying therapies. The research plan will focus on identifying genetic risk factors for the variation in neuropsychological profile of patients with AD. The major research aims of the application are 1) to identify common genetic variants associated with the difference between memory and non-memory function in AD using genome wide association (GWA), 2) to identify causal variants in genes implicated by the GWA in Aim 1 using whole exome sequencing (WES) data and 3) to identify A) gene x gene interactions among variants identified in aim 1 and variants previously found to be associated with incident AD and B) gene x environment interactions among variants identified in aim 1 and AD risk factors with environmental influences: education, hypertension and type 2 diabetes mellitus. The plan makes use of a large volume of genetic and neuropsychological data already obtained or in the process of being obtained through the AD Genetic Consortium, the National AD Sequencing Project, their associated parent studies and several additional studies. Sophisticated genetic and psychometric approaches will be employed to combine and analyze the datasets. The major training goals for Dr. Mez are 1) to develop proficiency in analyzing large-scale genetic data, especially WES data and 2) to learn and apply modern psychometric approaches, including item response theory, to analyze neuropsychological data. Dr. Mez is surrounded by a rich training environment at Boston University (BU). He is a member of the BU Alzheimer's Disease Center and is co-mentored by Dr. Neil Kowall, head of the center. He also is affiliated with the Biomedical Genetics Division in the Department of Medicine, headed by Dr. Lindsay Farrer, who serves as his primary mentor. Lastly he will receive training in psychometrics via frequent contact with Paul Crane, an expert in modern psychometric approaches, at the University of Washington, who will also serve as a co-mentor. The combination of Dr. Mez's current and growing expertise in dementia and the skills he will develop through this training grant will be rare for a clinician researcher, will greatly enhance his prospects for future R01 funding and will position him to lead a future multidisciplinary team focused on the genetics of dementing illnesses.

描述（由申请人提供）：本申请的总体目标是提供Jesse Mez博士，医学博士，M.S.在阿尔茨海默病（AD）遗传学领域的额外培训，使他可能发展成为一个独立的研究人员和多学科研究团队的熟练未来的领导者。Mez博士，他的导师和申请顾问设计了一个研究计划和补充培训计划，将使他参与几个新的研究领域，并为他提供领导具有不同专业知识的研究团队所需的技能。AD患者的临床表现可能存在很大差异。虽然已经确定了AD发病率的大量遗传风险因素，但很少有遗传风险因素被确定为AD临床表现的变化。 遗传风险因素提供了对潜在AD病理生理学的深入了解，并为疾病修饰疗法提供了潜在靶点。研究计划将集中于识别AD患者神经心理特征变化的遗传风险因素。本申请的主要研究目的是1）使用全基因组关联（GWA）鉴定与AD中记忆和非记忆功能之间的差异相关的常见遗传变异，2）使用全外显子组测序（WES）数据鉴定Aim 1中GWA所涉及的基因中的因果变体，和3）鉴定A）目的1中鉴定的变体与先前发现的与偶发AD相关的变体之间的基因x基因相互作用，和B）目的1中鉴定的变体与环境影响的AD风险因素之间的基因x环境相互作用：高血压和2型糖尿病。该计划利用了大量的遗传和神经心理学数据已经获得或正在获得通过AD遗传联盟，国家AD测序项目，其相关的母研究和几个额外的研究。将采用复杂的遗传学和心理测量学方法来联合收割机和分析数据集。Mez博士的主要培训目标是：1）熟练分析大规模遗传数据，特别是WES数据; 2）学习和应用现代心理测量方法，包括项目反应理论，分析神经心理学数据。Mez博士在波士顿大学（BU）拥有丰富的培训环境。他是BU阿尔茨海默病中心的成员，并由该中心的负责人Neil Kowall博士共同指导。他还隶属于医学系的生物医学遗传学部门，由林赛法雷尔博士领导，他是他的主要导师。最后，他将通过与华盛顿大学的现代心理测量方法专家Paul起重机的频繁接触接受心理测量学方面的培训，后者也将担任共同导师。Mez博士目前和不断增长的痴呆症专业知识和他将通过这项培训资助开发的技能相结合，对于临床研究人员来说将是罕见的，这将大大提高他未来R 01资金的前景，并将使他能够领导一个未来的多学科团队专注于痴呆症的遗传学。