EPAD:GRF Informationists Administrative Supplement

EPAD:GRF 信息主义者行政补充

• 批准号: 9319505
• 负责人: Paul K Crane
• 金额: $ 3.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319505
• 关键词: Accounting; Administrative Supplement; Adult; Aging; Alzheimer' s Disease; Architecture; Candidate Disease Gene; Clinical; Clinical Data; Cognition; Cognitive; Cohort Studies; Data; Data Set; Detection; Development; Diabetes Mellitus; Diagnosis; Disease; Elderly; Epidemiology; Executive Dysfunction; Funding Mechanisms; Genes; Genetic; Genetic Variation; Genotype; Goals; Health; Height; Heritability; Hypertension; Investigation; Knowledge; Late Onset Alzheimer Disease; Lead; Medical Genetics; Memory; Methods; Names; Nucleotides; Parents; Participant; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Prospective Studies; Psychometrics; Randomized; Religion and Spirituality; Research; Research Personnel; Risk; Risk Factors; Series; Time; Variant; Washington; Work; clinical epidemiology; disorder subtype; drug development; executive function; exome; exome sequencing; family structure; genetic analysis; genetic risk factor; genome sequencing; genome-wide; improved; neuropsychological; prospective; whole genome

DESCRIPTION (provided by applicant): Ten to 25% of people with late-onset Alzheimer's disease (AD) present with prominent executive deficits. Names such as frontal variant AD, executive prominent AD, and dysexecutive AD have been applied to this phenomenon. Little is known about traditional or genetic risk factors for dysexecutive AD. The overarching goal of this project is to further our understanding of the genetic architecture and clinical epidemiology of dysexecutive AD in the hopes of ultimately developing disease- modifying treatments. This project will leverage large-scale genome-wide genotype and sequence data and cognitive data collected on >17,000 participants across 19 collaborating studies. The investigators will use modern psychometric methods to co-calibrate cognitive data to develop scores on the same metric for memory and executive functioning. The investigators will use these scores to determine a continuous dysexecutive spectrum phenotype they have found to be highly heritable, with a pattern of heritability entirely distinct from that of AD. The investigators will leverage genome-wide genotype data for Aim 1. Five of the collaborating studies are prospective cohort studies with extensive cognitive and clinical data from >10,000 participants. The investigators will leverage these data for Aim 2. Several funding mechanisms are producing whole genome and whole exome sequencing data for people with AD. The investigators will leverage these data for Aim 3. Taken together, these investigations promise to improve what is known about dysexecutive AD, a highly heritable and devastating AD subtype. This work may identify genetic loci associated with risk for dysexecutive AD, which in turn may lead to development of drugs that could dramatically improve the lives of people with this condition.

描述（由申请人提供）：10% 至 25% 的晚发性阿尔茨海默病 (AD) 患者存在明显的执行缺陷。额叶变体 AD、执行突出 AD 和执行不良 AD 等名称已应用于这种现象。人们对执行障碍性 AD 的传统或遗传风险因素知之甚少。该项目的首要目标是进一步了解执行障碍性 AD 的遗传结构和临床流行病学，以期最终开发出疾病缓解疗法。该项目将利用 19 项合作研究中超过 17,000 名参与者收集的大规模全基因组基因型和序列数据以及认知数据。研究人员将使用现代心理测量方法来共同校准认知数据，以在记忆和执行功能的同一指标上得出分数。研究人员将利用这些分数来确定连续性执行障碍谱系表型，他们发现这种表型具有高度遗传性，其遗传模式与 AD 完全不同。调查人员将 利用全基因组基因型数据实现目标 1。其中五项合作研究是前瞻性队列研究，拥有超过 10,000 名参与者的广泛认知和临床数据。研究人员将利用这些数据实现目标 2。一些资助机制正在为 AD 患者提供全基因组和全外显子组测序数据。研究人员将利用这些数据实现目标 3。总而言之，这些研究有望改善对执行不良 AD（一种高度遗传性和破坏性 AD 亚型）的了解。这项工作可能会识别出与执行功能障碍风险相关的基因位点，这反过来又可能导致药物的开发，从而显着改善患有这种疾病的人的生活。