Elucidating the causal associations underlying Alzheimer's disease

阐明阿尔茨海默病的因果关系

• 批准号: 10335224
• 负责人: Shea J Andrews
• 金额: $ 12.32万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2022-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335224
• 关键词: Address; Advisory Committees; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Award; Big Data Methods; Biological; Blood Vessels; Cerebrovascular Trauma; Dementia; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease Progression; Economic Burden; Educational workshop; Elderly; Electronic Health Record; Epidemiology; Ethics; Etiology; Exposure to; Feedback; Foundations; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Health; Hippocampus (Brain); Hypertension; Incidence; Individual; Intervention; Knowledge; Leadership; Life Style; Literature; Mendelian randomization; Mental Depression; Mentors; Methodology; Methods; Minority Groups; Molecular; Nature; Neurodegenerative Disorders; Neurofibrillary Tangles; Obesity; Outcome; Parents; Pathogenesis; Persons; Phase; Phenotype; Population; Populations at Risk; Prevention; Proteins; Proxy; Random Allocation; Randomized Controlled Trials; Research; Research Personnel; Risk; Risk Factors; Senile Plaques; Smoking; Social isolation; Societies; Subgroup; Techniques; Testing; Therapeutic Intervention; Time; Training; Training Programs; Woman; aging population; apolipoprotein E-4; base; biobank; case control; cohort; disorder prevention; endophenotype; epidemiology study; experience; genetic analysis; genetic epidemiology; genetic variant; hearing impairment; lifestyle factors; lifestyle intervention; modifiable risk; novel; offspring; phenome; physical inactivity; polygenic risk score; prevent; programs; psychosocial; sex; skills; successful intervention; symposium; tau Proteins; tau-1; trait

Project Summary Alzheimer’s disease (AD) is a global crisis facing the aging population and society as a whole. With the number of people living with AD predicted to rise dramatically in the coming decades, it is imperative to pursue research that aims to reduce the expected incidence of dementia, such as identifying modifiable risk factors for lifestyle interventions. A prerequisite to establishing lifestyle interventions is demonstrating a causal effect of the proposed exposure (a risk factor) on AD or AD endophenotypes. The overarching objective of this research program is to enhance our understanding of the causal relationships underlying Alzheimer’s disease by utilizing genetically informed causal inference methods. We will use state-of-the-art techniques in statistical genetics that exploit the polygenic risk scoring (PRS) and Mendelian randomization (MR) approaches. PRS provide an estimate of an individual's genetic propensity to a trait and can be used to infer genetic overlap between phenotypes via predicting one phenotype from the PRS of another. The first aim will identify traits that have a shared genetic etiology with AD outcomes by conducting a phenome-wide PRS analysis. This will prioritize putative disease-modifying traits for AD outcomes. The second aim will conduct an MR phenome-wide association study to identify novel risk factors for AD that have not been identified using previous epidemiological approaches, while prioritizing hypotheses identified in the current literature (e.g. vascular health). MR uses genetic variants as proxies for exposures to provide an estimate of the causal association between an intermediate exposure and an outcome and conceptually similar to a ‘genetic randomized control trial’ due to the random allocation of genotypes from parents to offspring. In the final aim, PRS and MR will be used to determine if individual risk factors differentially contribute to the development of AD in at-risk subgroups by performing sex, ancestry, age, and APOE ε4 stratified analyses to identify subgroup- specific risk profiles and predictors. The proposed research will elucidate the risk factors underlying AD, which will have a significant impact on the development of lifestyle interventions to prevent AD and may explain differences in risk by sex and ancestry. Under the guidance of his mentor Dr. Alison Goate and co-mentor Dr. Kristine Yaffe, and a team of other advisors, Dr. Andrews will pursue a rigorous training program to accomplish the aims of this award and to develop into an independent researcher. This training will focus on developing skills in (1) causal inference, (2) big data analytics, (3) computational genomics, and (4) professional development. Development in these domains will be accomplished via coursework, attendance at conferences and workshops, gaining experience in providing mentoring and leading teams, and regular feedback from his advisory committee. Overall, the proposed study addresses a crucial and timely unmet need, and the additional skills developed during this award will provide a strong foundation for the candidate to establish independent leadership in the genetic epidemiology of Alzheimer’s disease.

项目摘要 阿尔茨海默氏病（AD）是整个人口和社会面临的全球危机。与数字 在未来几十年中，与AD的人预计将急剧上升，必须进行研究 旨在减少痴呆症的预期事件，例如确定可改变的生活方式风险因素 干预措施。建立生活方式干预措施的先决条件是证明 提议的AD或AD内表型暴露（一种风险因素）。这项研究的总体目标 计划是为了增强我们对阿尔茨海默氏病的因果关系的理解 利用一般知情的因果推理方法。我们将在 利用多基因风险评分（PRS）和门德尔随机化（MR）的统计遗传学 方法。 PRS提供了个人对特征的遗传倾向的估计，可用于推断 通过从另一个PR中预测一种表型之间的表型之间的遗传重叠。第一个目标 通过进行全现场PRS来识别具有具有AD结果的共享遗传病因的特征 分析。这将优先考虑针对AD结果的推定疾病改良特征。第二个目标将进行 MR现象全面的关联研究，以识别尚未使用使用的新的AD风险因素 先前的流行病学方法，同时优先考虑当前文献中确定的假设（例如 血管健康）。 MR使用遗传变异作为暴露的代理，以提供因果关系的估计值 中间暴露与结果之间的关联，并在概念上与“遗传”相似 由于基因型从父母到后代的随机分配，随机对照试验'。在最终目标中， PRS和MR将用于确定个体风险因素是否对AD的发展有所不同 通过进行性，祖先，年龄和APOEε4进行分层分析，以识别亚组 - 特定的风险概况和预测因素。拟议的研究将阐明AD的危险因素， 将对生活方式干预措施的发展产生重大影响，以防止AD，并可能解释 性别和血统风险差异。在他的心理艾莉森博士和同事博士的指导下 克里斯汀·耶夫（Kristine Yaffe）和其他顾问团队，安德鲁斯（Andrews）博士将继续进行严格的培训计划以完成 该奖项的目的并发展成为独立的研究人员。该培训将重点放在发展 （1）因果推断，（2）大数据分析，（3）计算基因组学和（4）专业的技能 发展。这些领域的发展将通过课程工作，参加会议来完成 和讲习班，获得提供心理和领导团队的经验，以及他的定期反馈 咨询委员会。总体而言，拟议的研究解决了至关重要，及时的未满足需求，以及其他 该奖项中开发的技能将为候选人建立独立的稳固基础 阿尔茨海默氏病遗传流行病学的领导能力。

项目成果

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity.

• DOI: 10.1016/j.ebiom.2021.103277
• 发表时间: 2021-03
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Fadista J;Kraven LM;Karjalainen J;Andrews SJ;Geller F;COVID-19 Host Genetics Initiative;Baillie JK;Wain LV;Jenkins RG;Feenstra B
• 通讯作者: Feenstra B