Genetics of aging, health and longevity: focus on regulatory mechanisms and functional variants connecting aging and Alzheimer's disease

该项目的目的是显著提高我们对阿尔茨海默病(AD)的异质性以及衰老和AD中常见的遗传机制的理解，并为AD预防寻找新的基因靶点，重点关注与衰老和AD有关的调控和稀有功能变异。这一目标将使用在几项纵向和横断面人类研究中收集的数据来实现，这些研究总共收集了50多万人的遗传和表型信息。具体目标：目标1.确定同时影响衰老和AD特征的新的多效性变异，并评估它们对AD风险和存活率的联合影响。我们将使用PheWas方法选择这些多效性SNPs，并使用估计遗传交互作用联合效应的新方法(交互作用多基因风险评分，IPRS)来评估它们对AD和生存的集体影响。我们还将指定富含各自基因的途径，并建议它们与阿尔茨海默病的联系机制。目的2.利用相关生物学途径的候选基因，研究生理性衰老与阿尔茨海默病的共同遗传机制，为防治阿尔茨海默病提供新的靶点。我们的假设是，在与衰老和AD相关的同一生物途径/过程中连接的基因将协同工作，并共同显著影响AD的特征，特别是在有加速身体衰老迹象的人中。在现有文献的基础上，我们将选择代表与衰老相关、也与AD相关的途径的候选基因集(例如，线粒体生物合成随着年龄的增长而下降，并且在AD中也(加剧))，以及影响各自基因和蛋白质水平翻译的调节元件，如miRNAs。然后，我们将评估这些基因对衰老和AD特征的联合效应(加法、GXG、IPRS)，包括在具有加速衰老迹象的个体的亚样本中，并选择候选遗传靶标，这些候选遗传靶标将在AIM 3中进一步验证。AIM 3.使用AD病理的生物标记物对AIMS 1、2中选择的候选遗传靶标进行临床前验证，并进一步探索观察到的关联的机制。我们将评估选定的变种对海马体体积、脑脊液和代谢(FDG)生物标记物的影响，以及考虑其他协变量对认知分数的影响。我们还将使用孟德尔随机化和相关方法，进一步探索目标1和2中选择的遗传因素与衰老和阿尔茨海默病表型之间的因果关系。该项目的成果将显著

The objective of this project is to significantly improve our understanding of the heterogeneity of Alzheimer’s disease (AD) and common genetic mechanisms in aging and AD, and find new genetic targets for AD prevention, with emphasis on regulatory and rare functional variants involved in both aging and AD. This objective will be addressed using data collected in several longitudinal and cross-sectional human studies with genetic and phenotypic information on more than half a million individuals in total. Specific Aims: Aim 1. Identify new pleiotropic variants that influence both aging and AD traits, and evaluate their joint impacts on AD risk and survival. We will select such pleiotropic SNPs, using PheWas approach, and evaluate their collective impacts on AD and survival, using new methods of estimating joint effects of genetic interactions (Interaction Polygenic Risk Scores, IPRS). We will also specify pathways enriched in respective genes, and suggest mechanisms connecting them to AD. Aim 2. Investigate shared genetic mechanisms between physiological aging and AD, using candidate genes from relevant biological pathways, and suggest new targets for AD prevention. Our hypothesis is that genes, which products are connected in the same biological pathway/process relevant to both aging and AD, will work in concert and jointly significantly influence AD traits, especially in people with signs of accelerated physical aging. Based on current literature, we will select sets of candidate genes representing pathways that were linked to aging, and also relevant to AD (e.g., mitochondrial biogenesis declines with aging, and also (exacerbated) in AD), and regulatory elements such as miRNAs that influence translation of respective genes and protein levels. Then we will evaluate joint effects (additive, GxG, IPRS) of these genes on aging and AD traits, including in subsamples of individuals with signs of accelerated aging, and select candidate genetic targets that will be further validated in Aim 3. Aim 3. Preclinical validation of candidate genetic targets selected in Aims 1, 2, using biomarkers of AD pathology, and further exploration of mechanisms of observed associations. We will estimate effects of the selected variants on hippocampal volume, CSF and metabolic (FDG) biomarkers, and on cognitive scores, considering other covariates. We will also further explore causal relationships between genetic factors selected in Aims 1 and 2, and phenotypes of aging and AD, using Mendelian Randomization and related approaches. Results of this project will significantly