Elucidating the causal associations underlying Alzheimer's disease

项目摘要 阿尔茨海默病(AD)是老龄化人口和整个社会面临的全球性危机。带着这个号码 预计未来几十年阿尔茨海默病患者的比例将急剧上升，进行研究是当务之急 这旨在降低痴呆症的预期发病率，例如确定生活方式的可改变的风险因素 干预措施。建立生活方式干预的先决条件是证明 建议暴露于AD或AD内表型(一个危险因素)。这项研究的首要目标是 计划的目的是通过以下方式加强我们对阿尔茨海默病背后的因果关系的理解 利用遗传知情的因果推理方法。我们将使用最先进的技术 利用多基因风险评分(PRS)和孟德尔随机化(MR)的统计遗传学 接近了。PR提供了个体对某一性状的遗传倾向的估计，并可用于推断 通过预测一种表型和另一种表型的表型之间的遗传重叠。第一个目标是 通过进行表型范围的PR来识别与AD结果具有相同遗传病因的特征 分析。这将优先考虑AD结果中假定的疾病修正特征。第二个目标将进行 磁共振全表型关联研究，以确定AD的新危险因素，尚未使用 以前的流行病学方法，在确定当前文献中确定的假设的优先顺序的同时(例如， 血管健康)。MR使用基因变异作为暴露的替代指标，以提供原因的估计 中间接触和结果之间的联系，在概念上类似于 “随机对照试验”，这是由于从父母到后代的基因随机分配。在最终的目标中， PR和MR将被用来确定个体风险因素是否对AD的发展有不同的贡献 在高危亚组中，通过执行性别、祖先、年龄和载脂蛋白ε4分层分析来确定亚组- 具体的风险概况和预测因素。拟议的研究将阐明AD背后的风险因素， 将对预防AD的生活方式干预措施的发展产生重大影响，并可能解释 不同性别和血统的风险差异。在他的导师艾莉森·戈特博士和共同导师艾莉森·戈特博士的指导下， 克里斯汀·亚菲和其他顾问团队，安德鲁斯博士将进行严格的培训计划，以完成 这一奖项的目标是发展成为一名独立的研究人员。本次培训的重点将是开发 具备(1)因果推理、(2)大数据分析、(3)计算基因组学和(4)专业技能 发展。这些领域的发展将通过课程作业、参加会议来完成 和研讨会，在提供指导和领导团队方面获得经验，并定期从他的 咨询委员会。总体而言，拟议的研究解决了一个关键和及时的未得到满足的需求，以及额外的 在此奖项期间培养的技能将为候选人建立独立的 在阿尔茨海默病遗传流行病学方面处于领先地位。

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.