Administrative Component

行政部分

• 批准号: 10840214
• 负责人: Michael A. Province
• 金额: $ 868.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10840214
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Automobile Driving; Big Data; Biological; Biological Markers; Blood Pressure; Budgets; Cardiovascular Diseases; Cognition; Cohort Studies; Collaborations; Communication; Communities; Complex; Data; Data Analyses; Data Collection; Data Set; Dementia; Denmark; Diabetes Mellitus; Diagnosis; Disease; Disease Resistance; Educational workshop; Enrollment; Family; Family Study; Foundations; Generations; Genes; Goals; Hand Strength; Home visitation; Institutional Review Boards; Life; Logistics; Longevity; Malignant Neoplasms; Measures; Medical; Methods; Monitor; Observational Study; Participant; Pathway interactions; Pattern; Persons; Phenotype; Process; Proteomics; Publications; Quality Control; Registries; Research; Research Personnel; Running; Sampling Studies; Site; Specificity; Systems Biology; Training; Universities; Untranslated RNA; Variant; Visit; Washington; cognitive performance; cohort; data cleaning; data integration; data sharing; deep sequencing; electronic data; experience; follow-up; genetic linkage; genetic linkage analysis; genetic pedigree; genetic signature; genetic variant; genome sequencing; genome wide association study; grandchild; healthy aging; improved; meetings; metabolomics; methylomics; novel; novel marker; offspring; prevent; proband; protective allele; pulmonary function; quality assurance; rate of change; success; symposium; transcriptomics; web site; whole genome

The Long Life Family Study (LLFS) has enrolled 4,953 participants in 539 pedigrees in the USA and Denmark that are enriched for exceptional longevity, and has measured them longitudinally in two extensive in-home visits measuring key healthy aging phenotypes in all of the major domains of the aging process. We have demonstrated through many publications that selecting on longevity in the first (proband) generation, results in the second (offspring) generation being much healthier than average in many key phenotypes. However, the pedigrees are heterogeneous by phenotype, with different families showing familial clustering of protection in cognition, grip strength, pulmonary function, blood pressure, etc. Further, comprehensive linkage analysis of the LLFS sample identifies extremely strong genetic linkage peaks for cross-sectional as well as longitudinal trajectory rates of change phenotypes for a wide variety of healthy aging domains such as exceptional cognitive performance and lack of Alzheimer’s disease. These peaks are NOT explained by GWAS SNPs (or those that can be imputed by GWAS). Pedigree specific LODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. We propose to do Whole Genome Sequencing on this unique cohort, to identify the rare protective variants driving these strong linkage peaks. We propose to continue longitudinal assessment of the cohort with a third in-person visit, which will allow us to assess potential non-linear patterns of aging, and adding formal assessment of dementia diagnosis for Alzheimer’s Disease and other dementia types, which will increase specificity and power to discover and follow- up on protective variants against Alzheimer’s Disease and other dementia diagnoses. For pedigrees driving multiple strong linkage peaks, we also propose to phenotypically measure the third generation (grandchildren), as these are likely to carry more copies of the rare protective alleles running in these families, which will exponentially increase our power to resolve them. Preliminary evidence from the Danish Medical Registry suggests that, at least in Denmark, the protection persists into this third generation, with significantly lower rates of medical conditions across the disease spectrum. We also propose to do extensive transcriptomics, methylomics, and proteomics on these selected high linkage pedigrees, to begin to move from “statistically associated variants/loci” to the biological genes of action, since we expect most of the driving variants will be regulatory and non-coding. It is critical to find the modes of action of these rare protective variants. We also propose to do metabolomics on the entire LLFS cohort, longitudinally, with the goal of identifying novel biomarkers of healthy aging and resistance to diseases such as Alzheimer’s in this unusually heathy cohort. Combined with a systems biology/network approach to data integration of the proposed “Big Data”, such biomarkers would improve our power to detect even more novel protective genetic variants and identify the genetic signatures and pathways of genes conferring protection in this unique cohort to prevent onset of major diseases such as diabetes, cardiovascular disease, cancer and Alzheimer’s Disease and other dementia types.

长寿家庭研究(LLFS)已经招募了4953名参与者，来自美国和丹麦的539个家系 它们富含超乎寻常的寿命，并在两次广泛的家访中进行了纵向测量 在衰老过程的所有主要领域测量关键的健康衰老表型。我们有 通过许多出版物表明，选择第一代(先证者)的寿命会导致 第二代(后代)在许多关键表型上比平均水平健康得多。然而， 家系在表型上是不同的，不同的家系表现出保护的家系聚集性。 认知、握力、肺功能、血压等。进一步，综合联动分析 LLFS样本确定了横截面和纵向极强的遗传连锁峰 各种健康衰老领域的表型变化率轨迹，如异常认知 表现和缺乏阿尔茨海默病。这些峰值不能用GWASSNPs(或那些 可以归因于GWAS)。谱系特有的LOD和初步的深度测序表明这些峰 是由在选定的家系中运行的稀有的保护性变体驱动的。我们建议做全基因组 对这一独特的队列进行测序，以确定驱动这些强连锁峰的罕见保护性变异。我们 建议通过第三次面对面访问继续对队列进行纵向评估，这将使我们能够 评估潜在的非线性衰老模式，并添加对痴呆症诊断的正式评估 阿尔茨海默病和其他痴呆症类型，这将增加发现和跟踪的特异性和能力- 关于阿尔茨海默氏症和其他痴呆症诊断的保护性变体。对于驾驶血统的人来说 多个强连锁峰，我们还建议对第三代(孙辈)进行表型测定， 因为这些基因可能携带更多在这些家族中运行的稀有保护性等位基因的副本，这将 成倍增加我们解决这些问题的能力。来自丹麦医疗登记处的初步证据 这表明，至少在丹麦，这种保护持续到第三代，而保护率要低得多 整个疾病谱的医疗状况。我们还建议进行广泛的转录转录， 在这些选定的高连锁家系上的甲基组学和蛋白质组学，开始从 与生物基因相关的变异/基因座，因为我们预计大多数驱动变异将是 规范的和非编码的。找到这些稀有的保护性变异体的作用模式至关重要。我们也 建议纵向对整个LLFS队列进行代谢组学研究，目标是确定新的 在这个异常健康的队列中，健康衰老和对阿尔茨海默氏症等疾病的抵抗力的生物标记物。 结合系统生物学/网络方法对拟议的“大数据”进行数据整合，例如 生物标记物将提高我们检测更新的保护性遗传变异并识别 在这个独特的队列中赋予保护的基因的遗传特征和途径，以防止重大疾病的发生 糖尿病、心血管疾病、癌症和阿尔茨海默氏症等疾病以及其他类型的痴呆症。