Protective Genetic Variants for Alzheimer Disease in the Amish - RENEWAL

阿米什人阿尔茨海默病的保护性遗传变异 - RENEWAL

• 批准号: 10448612
• 负责人: Jonathan L Haines
• 金额: $ 160.44万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448612
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amish; Amyloid beta-Protein; Biological; Biological Markers; Blood specimen; COVID-19; Case-Control Studies; Chromosome 17; Clinical Trials; Cognition; Cognitive; Collaborations; Collection; Communities; DNA; Data; Data Set; Development; Disease; Education; Enrollment; Environmental Risk Factor; Family; Foundations; Founder Generation; Future; Gene Expression; Genetic Markers; Genetic Variation; Genomics; Genotype; Goals; Impaired cognition; In Vitro; Indiana; Individual; Light; Long COVID; Longitudinal Studies; Longitudinal cohort; Maps; Measures; Natural Immunity; Neurodegenerative Disorders; Neuropsychology; Occupations; Ohio; Participant; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Prevention; Process; RNA; Recording of previous events; Research; Research Design; Running; SARS-CoV-2 exposure; SARS-CoV-2 infection; SNP array; Sampling; Signal Transduction; Subgroup; Suggestion; Testing; Variant; base; biobank; case control; cognitive performance; cohort; data repository; design; druggable target; effective therapy; experience; follow-up; genetic association; genetic linkage analysis; genetic variant; genome wide association study; genomic biomarker; health data; high risk; in silico; induced pluripotent stem cell; insertion/deletion mutation; insight; neurofilament; novel; pre-clinical; preservation; progression marker; protective allele; protective factors; protein expression; rare variant; risk prediction model; risk variant; social health determinants; tau Proteins; tau-1

Alzheimer disease (AD) is a devastating neurodegenerative disorder that affects millions of individuals in the U.S. It has so far resisted attempts to develop effective therapies despite numerous (failed) clinical trials based on known targets, most identified over 20 years ago. While genomic research (e.g. the Alzheimer’s Disease Sequencing Project; ADSP) has identified numerous additional risk loci, these results derive primarily from case- control datasets. In contrast, cohorts designed to identify variants that may protect from AD, and those using complementary study designs, are few. We used our extensive experience with the Amish communities in Indiana and Ohio to establish a cohort of older individuals at high risk of developing AD but who are cognitively unimpaired (CU). The Amish provide a unique opportunity to identify protective variants for AD because of their reduced background genetic variation and environmental risk factors. Their small founding population and endogamy provides enrichment for rare variants. Founder populations also enable testing for non-additive allelic effects and can magnify sub-significant association signals identified in case-control studies. The stability and engagement of our Amish participants enables longitudinal assessments of cognition and biomarkers. Our primary goals are to identify AD protective loci and characterize pre-clinical biomarkers of progression to cognitive impairment. Building on our existing large cohort, our replicated protective locus and several suggestive protective loci, and our existing biobank of DNA and plasma and databank of GWAS and WGS, we propose to: 1) Perform longitudinal assessment of cognition in our family-based Amish cohort; 2) Identify protective factors for AD and predictors of progression to cognitive impairment by analyzing genomic and longitudinal cognitive, biomarker, and SDOH data; and 3) Examine the functional implications of current and novel genes and variants by prioritizing loci using in silico annotation for functional consequences followed by in vitro functional characterization. Our results will identify potential druggable targets and accelerate the development of better treatments for AD.

阿尔茨海默氏病（AD）是一种毁灭性的神经退行性疾病，影响数百万个个体 到目前为止 关于已知目标，大多数在20年前被确定。而基因组研究（例如，阿尔茨海默氏病 测序项目； ADSP）已经确定了许多额外的风险基因座，这些结果来自病例 - 控制数据集。相比之下，旨在识别可以保护AD的变体的同类人群，以及使用的变体 互补的研究设计很少。我们在阿米什人社区中使用了丰富的经验 印第安纳州和俄亥俄州建立一群具有高风险发展广告但认知上的老年人 独立的（CU）。阿米什人提供了一个独特的机会来识别广告的受保护变体，因为它们 背景遗传变异和环境风险因素减少。他们的成立人群和 内婚为稀有变体提供富集。创始人人口还可以对非加addive Allic进行测试 效应并可以放大在病例对照研究中确定的亚物质相关信号。稳定性和 我们的阿米什人参与者的参与可以对认知和生物标志物进行纵向评估。我们的 主要目标是确定受保护的本地保护，并表征前临床前的生物标志物的进展 认知障碍。在我们现有的大型队列的基​​础上，我们被复制的受保护基因座和一些暗示性 保护区域以及我们现有的DNA，等离子体和GWAS和WGS数据库的生物库，我们建议： 1）对我们家庭基于家庭的阿米什人队列进行认知的纵向评估； 2）确定保护因素 用于通过分析的基因组和纵向认知的进展到认知障碍的预测指标 生物标志物和SDOH数据； 3）检查当前和新基因和变体的功能含义 通过在计算机注释中使用基因座的优先级，用于功能后果，然后是体外功能 表征。我们的结果将确定潜在的可吸毒目标并加速更好 广告的治疗方法。