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: 8765480
• 负责人: Jesse Benjamin Mez
• 金额: $ 13.04万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765480
• 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; Learning; 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; Relative (related person); Research; Research Personnel; Risk Factors; Speed; Staging; Training; Universities; Variant; Washington; Work; base; design; drug development; executive function; exome sequencing; genetic risk factor; genetic variant; genome wide association study; genome-wide; insight; member; multidisciplinary; neuroimaging; neuropsychological; 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向 Jesse Mez 博士（医学博士、理学硕士）提供在阿尔茨海默病 (AD) 遗传学领域接受额外培训，以便他能够发展成为一名独立研究者和多学科研究团队的熟练未来领导者。梅兹博士、他的导师和申请顾问设计了一项研究计划和补充培训计划，这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显着差异虽然已经确定了相当多的AD发病的遗传风险因素，但很少有遗传风险因素被确定为AD临床表现的差异。 遗传风险因素提供了对 AD 病理生理学的深入了解，并为疾病缓解疗法提供了潜在的目标。该研究计划将侧重于确定 AD 患者神经心理学特征变化的遗传风险因素。该应用程序的主要研究目标是 1) 使用全基因组关联 (GWA) 识别与 AD 记忆和非记忆功能差异相关的常见遗传变异，2) 识别 Aim 中 GWA 涉及的基因中的因果变异1 使用全外显子组测序 (WES) 数据和 3) 识别 A) 目标 1 中确定的变体之间的基因 x 基因相互作用以及之前发现与 AD 事件相关的变体和 B) 目标 1 中确定的变体之间的基因 x 环境相互作用广告受环境影响的危险因素：教育、高血压和2型糖尿病。该计划利用了通过 AD 基因联盟、国家 AD 测序项目、其相关的母体研究和其他几项研究已经获得或正在获得的大量遗传和神经心理学数据。将采用复杂的遗传和心理测量方法来组合和分析数据集。 Mez 博士的主要培训目标是 1) 提高分析大规模遗传数据（尤其是 WES 数据）的能力；2) 学习和应用现代心理测量方法（包括项目反应理论）来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。他是波士顿大学阿尔茨海默病中心的成员，并由该中心主任 Neil Kowall 博士共同指导。他还隶属于医学系生物医学遗传学部门，该部门由 Lindsay Farrer 博士领导，也是他的主要导师。最后，他将通过与华盛顿大学现代心理测量方法专家 Paul Crane 的频繁接触来接受心理测量学培训，Paul Crane 也将担任联合导师。 Mez 博士目前在痴呆症方面的专业知识和不断增长的专业知识以及他将通过这项培训资助培养的技能对于临床研究人员来说是罕见的，这将大大增强他未来 R01 资助的前景，并使他能够领导一个未来的多学科团队，重点关注关于痴呆症的遗传学。