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.

阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，影响世界上数百万人。 美国迄今为止，尽管有许多（失败的）临床试验， 大多数是20多年前确定的虽然基因组研究（例如阿尔茨海默病 测序项目; ADSP）已经确定了许多额外的风险位点，这些结果主要来自病例- 控制数据集。相比之下，设计用于识别可能保护免受AD的变体的队列，以及那些使用 互补的研究设计很少。我们利用我们在阿米什社区的丰富经验， 印第安纳州和俄亥俄州建立一个老年人队列，这些老年人有患AD的高风险，但认知功能正常。 未受损（CU）。阿米什人提供了一个独特的机会，以确定保护性变异的AD，因为他们的 减少背景遗传变异和环境风险因素。他们的小创始人口和 内婚为稀有变异体提供了富集。创始人群体还能够检测非加性等位基因 影响，并可以放大病例对照研究中确定的次显著相关信号。的稳定性和 我们的阿米什参与者的参与使认知和生物标志物的纵向评估成为可能。我们 主要目的是鉴定AD保护基因座，并表征进展至 认知障碍基于我们现有的大型队列，我们复制的保护基因座和几个提示性的基因座， 保护基因座，以及我们现有的DNA和血浆生物库以及GWAS和WGS数据库，我们建议： 1)在我们以家庭为基础的阿米什人队列中进行认知的纵向评估; 2）确定保护因素 通过分析基因组和纵向认知， 生物标志物和SDOH数据;以及3）检查当前和新基因和变体的功能含义 通过使用用于功能性结果的计算机注释优先化基因座，然后使用体外功能性结果， 特征化我们的研究结果将确定潜在的药物靶点，并加速开发更好的药物。 治疗AD。