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

衰老、健康和长寿的遗传学：关注衰老与阿尔茨海默病之间的调节机制和功能变异

• 批准号: 10118665
• 负责人: ALEXANDER M KULMINSKI
• 金额: $ 50.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118665
• 关键词: Address; Age; Aging; Air Pollution; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Biogenesis; Biological; Biological Markers; Brain; Candidate Disease Gene; Cells; Cognitive; Complex; Data; Disease; Education; Gender; Gene Proteins; Genes; Genetic; Health; Heterogeneity; Hippocampus (Brain); Human; Individual; Joints; Ligands; Link; Literature; Longevity; Metabolic; Methods; MicroRNAs; Mitochondria; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Play; Process; Proteins; Race; Randomized; Regulatory Element; Role; Smoking; Specific qualifier value; Testing; Tissues; Translations; Validation; Variant; Work; base; candidate validation; disease heterogeneity; exome sequencing; experimental study; genetic analysis; genetic variant; human data; improved; individualized prevention; normal aging; personalized medicine; polygenic risk score; pre-clinical; receptor; resilience; senescence; trait

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

该项目的目标是显著提高我们对阿尔茨海默病（AD）异质性以及衰老和AD中常见遗传机制的理解，并为AD预防找到新的遗传靶点，重点是参与衰老和AD的调节和罕见功能变体。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解决，这些研究总共涉及50多万人的遗传和表型信息。具体目标：目标1。识别影响衰老和AD特征的新的多效性变体，并评估其对AD风险和生存的联合影响。我们将使用PheWas方法选择这种多效性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。我们还将详细说明在各自的基因丰富的途径，并建议将它们连接到AD的机制。目标2.研究生理衰老和AD之间的共同遗传机制，使用相关生物学途径的候选基因，并提出预防AD的新靶点。我们的假设是，在与衰老和AD相关的相同生物学途径/过程中连接的基因，将协同工作并共同显著影响AD特征，特别是在具有加速身体衰老迹象的人中。基于目前的文献，我们将选择代表与衰老相关的途径的候选基因集，并且也与AD相关（例如，线粒体生物合成随着衰老而下降，并且在AD中也（加剧）），以及调节元件，如影响相应基因和蛋白质水平的翻译的miRNA。然后，我们将评估这些基因对衰老和AD特征的联合效应（加性，GxG，IPRS），包括具有加速衰老迹象的个体的子样本，并选择将在目标3中进一步验证的候选遗传靶点。目标3.使用AD病理学的生物标志物对目的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相关性的机制。我们将评估所选变异对海马体积、CSF和代谢（FDG）生物标志物以及认知评分的影响，同时考虑其他协变量。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AD表型之间的因果关系。该项目的成果将显著