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: 10618201
• 负责人: ALEXANDER M KULMINSKI
• 金额: $ 49.04万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618201
• 关键词: Acceleration; 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; Genes; Genetic; Health; Heterogeneity; Hippocampus; Human; Individual; Joints; Ligands; Link; Literature; Longevity; Mendelian randomization; Metabolic; Methods; MicroRNAs; Mitochondria; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Play; Process; Proteins; Race; Regulatory Element; Role; Smoking; Specific qualifier value; Testing; Tissues; Translations; Validation; Variant; Work; candidate selection; candidate validation; disease heterogeneity; exome sequencing; experimental study; 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

该项目的目标是显着提高我们对阿尔茨海默病 (AD) 异质性以及衰老和 AD 常见遗传机制的理解，并找到预防 AD 的新遗传靶点，重点关注与衰老和 AD 相关的调节和罕见功能变异。这一目标将通过多项纵向和横断面人类研究中收集的数据来实现，这些数据涉及总共超过 50 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 特征的新多效性变异，并评估它们对 AD 风险和生存的联合影响。我们将使用 PheWas 方法选择此类多效性 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。我们还将具体说明各自基因中富集的途径，并提出将它们与 AD 连接的机制。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 相关的同一生物途径/过程中相连）将协同工作，共同显着影响 AD 特征，特别是对于有加速身体衰老迹象的人。根据现有文献，我们将选择代表与衰老相关且与 AD 相关的途径的候选基因组（例如，线粒体生物合成随着衰老而下降，并且在 AD 中也（加剧）），以及影响各个基因翻译和蛋白质水平的调控元件，例如 miRNA。然后，我们将评估这些基因对衰老和 AD 性状的联合效应（加性、GxG、IPRS），包括在具有加速衰老迹象的个体子样本中，并选择将在目标 3 中进一步验证的候选遗传目标。目标 3. 使用 AD 病理学生物标志物对目标 1、2 中选择的候选遗传目标进行临床前验证，并进一步探索观察到的关联机制。我们将考虑其他协变量，估计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。我们还将利用孟德尔随机化和相关方法，进一步探讨目标 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。该项目的成果将显着