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: 10399467
• 负责人: ALEXANDER M KULMINSKI
• 金额: $ 49.59万
• 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/10399467
• 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; 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; 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

该项目的目的是显着提高我们对衰老和AD中阿尔茨海默氏病（AD）和常见遗传机制的异质性的理解，并找到了预防AD的新遗传靶标，重点是与衰老和AD相关的调节和稀有功能变体。该目标将使用在几个纵向和横截面人类研究中收集的数据来解决，并提供有关总共超过50万个人的遗传和表型信息。具体目的：目标1。确定影响衰老和AD特征的新的多效变体，并评估其对AD风险和生存的关节影响。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（相互作用多基因风险评分，IPR）的新方法来评估其对AD和生存的集体影响。我们还将指定富含相对基因的途径，并建议将它们连接到AD的机制。 AIM 2。使用来自相关生物学途径的候选基因研究物理衰老和AD之间的共享遗传机制，并提出了预防AD的新靶标。我们的假设是，与衰老和AD相关的相同生物学途径/过程相关的基因将共同起作用，并共同影响AD性状，尤其是在具有加速身体衰老迹象的人中。基于当前的文献，我们将选择代表与衰老相关的途径的一组候选基因，也与AD相关（例如，随着衰老的衰老而下降，AD中的线粒体生物发生下降，并且在AD中也（加剧），以及影响相对基因和蛋白质水平转化的miRNA等监管元素。然后，我们将评估这些基因对衰老和AD特征的关节效应（添加剂，GXG，IPRS），包括在具有加速衰老迹象的个体的子样本中，并选择将在AIM 3中进一步验证的候选遗传靶标3。AIM3。使用Alimake Issportiation的候选遗传学验证，并使用AD PATHORVIITS选择了AD PATHORVITION，并使用AD PATHOLOLICES和AD AD PARDOVITION进行了研究。我们将估计所选变体对海马体积，CSF和代谢（FDG）生物标志物以及认知评分的影响，考虑到其他协变量。我们还将使用孟德尔随机化和相关方法进一步探索在目标1和2中选择的遗传因素与衰老和AD的表型之间的因果关系。该项目的结果将大大