South Texas Alzheimer's Disease Center Genetics and Multiomics Core

南德克萨斯阿尔茨海默病中心遗传学和多组学核心

• 批准号: 10662350
• 负责人: Sudha Seshadri
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662350
• 关键词: ATAC-seq; Acceleration; Address; Affect; African American population; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Applied Genetics; Area; Astrocytes; Biological; Biological Markers; Biology; Blood; Brain; Cells; Cholesterol; Clinical; Clinical Trials; Collaborations; Communities; Comprehensive Health Care; Consensus; Consent; Creativeness; DNA; DNA Sequence Alteration; Data; Data Set; Dementia; Diagnosis; Disease; Disease Progression; Diverse Workforce; Elderly; Eligibility Determination; Endowment; Enrollment; Ensure; Ethics; Extended Family; Faculty; Family; Family history of; First Degree Relative; Funding; Genes; Genetic; Genetic Counseling; Genetic Diseases; Genetic Risk; Genetic Variation; Genomics; Genotype; Goals; Grant; Heart; Heterogeneity; Hispanic; Hispanic Americans; Hispanic Populations; Image; Individual; Inflammation; International; Magnetic Resonance Imaging; Medical; Medical Genetics; Methods; Methylation; Mexican Americans; Microglia; Mitochondria; Motor; Multiomic Data; Mutation; Neurons; Neurosciences; Not Hispanic or Latino; Nuclear Pore Complex; Office of Administrative Management; Oligodendroglia; Organoids; Participant; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Population Heterogeneity; Positron-Emission Tomography; Precision therapeutics; Prevention; Publications; Research; Research Methodology; Research Personnel; Research Support; Resources; Risk; Risk Estimate; Sampling; Science; Sensory; Serum; South Texas; Syndrome; Training; Training Programs; Validation; Work; biobank; biotypes; catalyst; cell type; clinical sequencing; cohort; data management; decrease resilience; digital; education research; follow-up; functional genomics; genetic variant; genome sequencing; genome wide association study; genomic data; genomic epidemiology; graduate student; improved; individual patient; individualized prevention; induced pluripotent stem cell; innovation; lipidomics; machine learning method; member; metabolomics; multiple omics; neuropathology; new therapeutic target; normal aging; novel; personalized medicine; phenotypic data; precision medicine; proband; prognostication; recruit; resilience; risk stratification; symposium; tau Proteins; therapeutic target; transcriptomics; usability; whole genome

Dementia in older adults is clinically, genetically and pathologically heterogeneous. Understanding this heterogeneity and addressing all the biological pathways that increase risk and lower resilience, will be required to provide precision prevention, diagnosis and treatment. Genome wide association studies (GWAS) have implicated over 40 genes, multiple cell and varied biological pathways (amyloid, tau, endolysosomal, mitochondrial function, inflammation). Genetic and multiomic characterization of ADRD in individuals, and in groups of patients, could exploit this heterogeneity towards more effective, precise, personalized prevention and treatment of dementia. Whereas, most of these biological discoveries have been in non-Hispanic whites, there is a paucity of data on Mexican American (MA) Hispanics, who are the fastest growing segment of older adults in the US. The Genetics and Multiomics Core (GMC) of the South Texas Alzheimer Disease Consortium (STAC) has the following specific aims: Aim 1: Identifying causal genetic variation underlying ADRD in CC enrollees through a combination of routine clinical sequencing and a ‘Undiagnosed Disease Network’ approach to identifying novel genetic variation that may be causal or contributory. To achieve this, we will record results of clinical sequencing and genetic counseling in proband and relatives. Aim 2: Genetically characterize all CC enrollees (using APOE and GWAS) to expand our understanding of genetic variation modifying risk, resilience and disease progression. We will aim to refine and improve genetic risk estimates for late onset AD, PD, DLB permitting more accurate risk stratification in MA Hispanics, better targeting for recruitment in clinical trials. Aim 3: Serve as a resource for STAC investigators, trainees, and the national ADRD research community for deeply phenotyped Hispanic MA samples, genomic data and innovative analysis methods. To achieve this (i) GMC will share DNA, genetic and phenotypic data (clinical, MRI and PET imaging, blood and CSF -amyloid, tau, inflammation, metabolomic, lipidomic- and sensory-motor biomarkers) and digital and conventional neuropathology, through NCRAD, NIAGADS, NACC; (ii) GMC will serve as a STAC resource for providing methylation, transcriptomics (blood, brain, CSF), ATAC-Seq, single-cell omics data and for generating usable iPSCs and organoids; (iii) GMC will develop and share innovative genetic and multiomic association analyses methods, especially for use in large families; (iv) GMC will facilitate collaborations with consortia such as the Alzheimer Disease Genetics Consortium (ADGC), the International Genomics of AD Project (IGAP), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and Transomics in Precision Medicine (TOPMed); (v) GMC faculty and resources will support the Research Education Core in developing a diverse workforce, well-trained in applying genetic and multiomic research methods.

老年人痴呆症在临床、遗传和病理学上具有异质性。了解这一点 异质性并解决所有增加风险和降低复原力的生物途径，将是 精准预防、精准诊断、精准治疗。全基因组关联研究（GWAS） 涉及 40 多个基因、多个细胞和不同的生物途径（淀粉样蛋白、tau、内溶酶体、 线粒体功能、炎症）。 ADRD 在个体和个体中的遗传和多组学特征 患者群体可以利用这种异质性来实现更有效、精确、个性化的预防 和痴呆症的治疗。然而，大多数这些生物学发现都是在非西班牙裔白人身上进行的， 关于墨西哥裔美国人 (MA) 西班牙裔的数据很少，他们是老年人中增长最快的群体 在美国的成年人。南德克萨斯阿尔茨海默病的遗传学和多组学核心 (GMC) 联盟（STAC）有以下具体目标： 目标 1：通过结合以下方法来识别 CC 参与者中 ADRD 的因果遗传变异 常规临床测序和“未确诊疾病网络”方法来识别新的遗传基因 可能是因果性或促成性的变异。为了实现这一目标，我们将记录临床测序的结果和 先证者及其亲属的遗传咨询。 目标 2：对所有 CC 参与者进行基因表征（使用 APOE 和 GWAS）以扩展我们的研究 了解遗传变异会改变风险、恢复力和疾病进展。我们将致力于精益求精 改善迟发性 AD、PD、DLB 的遗传风险估计，从而可以更准确地进行风险分层 MA 西班牙裔，更好地针对临床试验招募。 目标 3：为 STAC 研究人员、学员和国家 ADRD 研究提供资源 深度表型西班牙裔 MA 样本、基因组数据和创新分析方法的社区。 为了实现这一目标 (i) GMC 将共享 DNA、遗传和表型数据（临床、MRI 和 PET 成像、 血液和脑脊液（淀粉样蛋白、tau蛋白、炎症、代谢组学、脂质组学和感觉运动生物标志物）和数字 和传统神经病理学，通过 NCRAD、NIAGADS、NACC； (ii) GMC 将担任 STAC 提供甲基化、转录组学（血液、大脑、CSF）、ATAC-Seq、单细胞组学数据和 用于生成可用的 iPSC 和类器官； (iii) GMC 将开发和分享创新的遗传和多组学 关联分析方法，特别适用于大家庭； (iv) GMC 将促进与 联盟，例如阿尔茨海默病遗传学联盟 (ADGC)、国际 AD 基因组学联盟 项目 (IGAP)、基因组流行病学心脏和衰老研究队列 (CHARGE) 和跨组学 精准医学（TOPMed）； (v) GMC 教职员工和资源将支持研究教育核心 培养一支多元化的劳动力队伍，在应用遗传和多组学研究方法方面接受过良好的培训。