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: 10270731
• 负责人: Sudha Seshadri
• 金额: $ 25.68万
• 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/10270731
• 关键词: ATAC-seq; Address; Affect; African American; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Area; Astrocytes; Biological; Biological Markers; Biology; Blood; Brain; Cells; Cholesterol; Clinical; Clinical Trials; Collaborations; Communities; Comprehensive Health Care; Consensus; Consent; DNA; DNA Sequence Alteration; Data; Data Analyses; 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 Americans; Hispanics; Individual; Inflammation; International; Lead; 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; Research; Research Methodology; Research Personnel; Research Support; Resources; Risk; Risk Estimate; Sampling; Science; Sensory; Serum; South Texas; Syndrome; Training; Training Programs; Validation; Work; biobank; catalyst; cell type; clinical sequencing; cohort; data management; digital; education research; follow-up; functional genomics; genetic association; genetic variant; genome sequencing; genome wide association study; genomic data; genomic epidemiology; graduate student; imaging biomarker; 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; prognostic; ranpirnase; recruit; resilience; risk stratification; symposium; tau Proteins; therapeutic target; transcriptomics; 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.

老年痴呆症在临床、遗传和病理上是异质性的。理解这一 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 需要提供精确的预防、诊断和治疗。全基因组关联研究（GWAS） 涉及超过40个基因、多个细胞和多种生物学途径（淀粉样蛋白、tau蛋白、内溶酶体， 线粒体功能、炎症）。ADRD在个体中的遗传和多组学特征， 可以利用这种异质性进行更有效、精确、个性化的预防 和痴呆症的治疗。然而，大多数生物学发现都是在非西班牙裔白人身上发现的， 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部分。 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） 联合会（STAC）有以下具体目标： 目的1：通过以下方法的组合，确定CC入组者中ADRD潜在的因果遗传变异： 常规临床测序和“未诊断疾病网络”方法来识别新的遗传 可能是因果或促成的变化。为了实现这一目标，我们将记录临床测序的结果， 先证者及其亲属的遗传咨询。 目标2：对所有CC入组者进行遗传学表征（使用APOE和GWAS），以扩大我们的研究范围。 了解遗传变异改变风险、复原力和疾病进展。我们将致力于完善 并改善晚发AD、PD、DLB的遗传风险估计， MA西班牙裔，更好地针对临床试验中的招募。 目标3：作为STAC调查人员、受训人员和国家ADRD研究的资源 社区的深度表型西班牙裔MA样品，基因组数据和创新的分析方法。 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CSF -淀粉样蛋白、tau、炎症、代谢组学、脂质组学和感觉运动生物标志物）和数字 和传统的神经病理学，通过NCRAD，NIAGADS，NACC;（ii）GMC将作为STAC 提供甲基化、转录组学（血液、脑、CSF）、ATAC-Seq、单细胞组学数据和 用于产生可用的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，特别是在大家庭中使用;（四）GMC将促进与 如阿尔茨海默病遗传学联盟（ADGC）、国际AD基因组学联盟（International Genomics of AD）等。 项目（IGAP）、基因组流行病学（CHARGE）和转基因组学中的心脏和衰老研究队列 （五）GMC的教师和资源将支持研究教育核心， 发展一支在应用遗传和多组学研究方法方面训练有素的多样化劳动力队伍。