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: 10689703
• 负责人: Jonathan L Haines
• 金额: $ 157.71万
• 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/10689703
• 关键词: Acceleration; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; 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; Education; Enrollment; Environmental Risk Factor; Family; Foundations; Founder Generation; Future; Gene Expression; Genes; Genetic; 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; Testing; Variant; biobank; case control; cognitive performance; cohort; data integration; data repository; design; druggable target; effective therapy; experience; follow-up; genetic association; genetic linkage analysis; genetic variant; genome wide association study; 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) 是一种毁灭性的神经退行性疾病，影响着数以百万计的人 尽管进行了大量（失败的）临床试验，但美国迄今为止仍拒绝开发有效疗法的尝试 已知的目标，大多数是在 20 多年前在基因组研究中发现的（例如阿尔茨海默病）。 测序项目；ADSP）已确定了许多额外的风险位点，这些结果主要来自案例 - 相比之下，旨在识别可能预防 AD 的变体的队列以及使用的队列。 我们在阿米什社区中运用了丰富的经验，但补充性的研究设计很少。 印第安纳州和俄亥俄州将建立一组患有 AD 高风险但认知能力较差的老年人群体 未受损 (CU) 的阿米什人提供了一个独特的机会来识别 AD 的保护性变体，因为它们 减少了背景遗传变异和环境风险因素。 内婚制提供了稀有变异的富集，也使得非加性等位基因的测试成为可能。 效应，并可以放大病例对照研究中发现的次显着关联信号。 阿米什参与者的参与可以对认知和生物标志物进行纵向评估。 主要目标是确定 AD 保护性位点并表征进展为 AD 的临床前生物标志物 认知障碍建立在我们现有的大型队列、我们复制的保护位点和几个暗示性的基础上。 保护位点，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) 对我们以家庭为基础的阿米什队列进行认知纵向评估 2) 确定保护因素； 通过分析基因组和纵向认知来确定 AD 和认知障碍进展的预测因素， 生物标志物和 SDOH 数据；以及 3) 检查当前和新基因及变异的功能含义 通过优先使用计算机注释功能结果的位点，然后是体外功能 我们的结果将确定潜在的药物靶点并加速更好的药物的开发。 AD 的治疗。

项目成果

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

俄亥俄州和印第安纳州阿米什人阿尔茨海默病风险的遗传结构。

• 发表时间: 2022-07-14
• 作者: Osterman, Michael D;Song, Yeunjoo E;Adams, Larry D;Laux, Renee A;Caywood, Laura J;Prough, Michael B;Clouse, Jason E;Herington, Sharlene D;Slifer, Susan H;Lynn, Audrey;Fuzzell, M Denise;Fuzzell, Sarada L;Hochstetler, Sherri D;Miskimen, Kristy
• 通讯作者: Miskimen, Kristy

Sensitivity to differential NRF1 gene signatures contributes to breast cancer disparities.

对差异 NRF1 基因特征的敏感性导致乳腺癌差异。

• 发表时间: 2020-11
• 影响因子: 3.6
• 作者: Ramos, Jairo;Yoo, Changwon;Felty, Quentin;Gong, Zhenghua;Liuzzi, Juan P;Poppiti, Robert;Thakur, Indu Shekhar;Goel, Ruchika;Vaid, Ashok Kumar;Komotar, Ricardo Jorge;Ehtesham, Nasreen Z;Hasnain, Seyed E;Roy, Deodutta
• 通讯作者: Roy, Deodutta

Lower Levels of Education Are Associated with Cognitive Impairment in the Old Order Amish.

旧秩序阿米什人的教育水平较低与认知障碍有关。

• 发表时间: 2021
• 作者: Ramos, Jairo;Chowdhury, Aneesa R;Caywood, Laura J;Prough, Michael;Denise Fuzzell, M;Fuzzell, Sarada;Miskimen, Kristy;Whitehead, Patrice L;Adams, Larry D;Laux, Renee;Song, Yeunjoo;Ogrocki, Paula;Lerner, Alan J;Vance, Jeffery M;Haines, Jonatha
• 通讯作者: Haines, Jonatha

Psychometric approaches to defining cognitive phenotypes in the Old Order Amish.

定义旧秩序阿米什认知表型的心理测量方法。

• 发表时间: 2023-04
• 影响因子: 4
• 作者: Zaman, Andrew;Caywood, Laura;Prough, Michael;Clouse, Jason;Harrington, Sharlene;Adams, Larry;Fuzzell, Denise;Fuzzell, Sarada;Laux, Renee;Hochstetler, Sherri D;Ogrocki, Paula;Lerner, Alan;Vance, Jeffery M;Haines, Jonathan L;Scott, William K
• 通讯作者: Scott, William K

Visuospatial and Verbal Memory Differences in Amish Individuals With Alzheimer Disease and Related Dementias.

患有阿尔茨海默病和相关痴呆症的阿米什人的视觉空间和言语记忆差异。

• 发表时间: 2023-07-01
• 影响因子: 2.1
• 作者: Prough, Michael B;Zaman, Andrew;Caywood, Laura J;Clouse, Jason E;Herington, Sharlene D;Slifer, Susan H;Dorfsman, Daniel A;Adams, Larry A;Laux, Reneé A;Song, Yeunjoo E;Lynn, Audrey;Fuzzell, Denise;Fuzzell, Sarada L;Miller, Sherri D;Miskimen
• 通讯作者: Miskimen