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的共同遗传机制的认识，寻找新的AD预防基因靶点，重点关注衰老和AD相关的调节和罕见功能变异。这一目标将利用在几个纵向和横断面人类研究中收集的数据来解决，这些研究中有50多万人的遗传和表型信息。具体目标：目标1。确定影响衰老和AD特征的新的多效性变异，并评估它们对AD风险和生存的共同影响。我们将使用PheWas方法选择这些多效性snp，并使用估计遗传相互作用联合效应的新方法（相互作用多基因风险评分，IPRS）评估它们对AD和生存的集体影响。我们还将指定各自基因中富集的途径，并提出将它们与AD联系起来的机制。目标2。利用相关生物学途径的候选基因，研究生理衰老与AD之间的共同遗传机制，并提出AD预防的新靶点。我们的假设是基因，其产物在与衰老和AD相关的相同生物途径/过程中连接，将协同作用并共同显著影响AD特征，特别是在有加速身体衰老迹象的人群中。根据目前的文献，我们将选择一系列候选基因，这些基因代表与衰老相关的途径，也与阿尔茨海默病相关（例如，线粒体生物发生随着年龄的增长而下降，并且在阿尔茨海默病中（加剧）），以及影响各自基因翻译和蛋白质水平的调控元件，如mirna。然后，我们将评估这些基因对衰老和AD特征的联合效应（additive, GxG， IPRS），包括在具有加速衰老迹象的个体亚样本中，并选择候选基因靶点，这些靶点将在Aim 3中进一步验证。目标3。使用AD病理生物标志物对Aims 1,2中选择的候选遗传靶点进行临床前验证，并进一步探索观察到的关联机制。我们将在考虑其他协变量的情况下，评估所选变异对海马体积、脑脊液和代谢（FDG）生物标志物以及认知评分的影响。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和目标2中选择的遗传因素与衰老和AD表型之间的因果关系。这个项目的结果将显著

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