South Texas Alzheimer's Disease Center Genetics and Multiomics Core

老年人的痴呆症在临床、遗传和病理上是不同的。理解这一点 异质性和解决所有增加风险和降低弹性的生物途径将是 需要提供精准的预防、诊断和治疗。全基因组关联研究 涉及40多个基因，多个细胞和不同的生物通路(淀粉样蛋白，tau，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，以及 患者群体，可以利用这种异质性来进行更有效、更精确、更个性化的预防 以及痴呆症的治疗。然而，这些生物发现大多是在非西班牙裔白人身上发现的， 关于墨西哥裔美国人(MA)拉美裔的数据很少，他们是老年人中增长最快的部分 美国的成年人。南得克萨斯州阿尔茨海默病的遗传学和多组学核心(GMC) 联合体(STAC)有以下具体目标： 目标1：通过以下组合确定CC参与者ADRD潜在的因果遗传变异 用于鉴定新基因的常规临床测序和“未诊断疾病网络”方法 可能是有原因的或有贡献的变化。为了实现这一目标，我们将记录临床测序和 先证者及亲属的遗传咨询。 目标2：对所有CC参与者进行基因特征分析(使用APOE和GWAS)，以扩大我们的 了解基因变异改变风险、恢复力和疾病进展。我们将致力于完善 并改进晚发性AD、PD、DLB的遗传风险估计，从而在 更好地瞄准了临床试验中的招募对象。 目标3：作为STAC研究人员、受训人员和国家ADRD研究的资源 西班牙裔MA样本、基因组数据和创新分析方法的深度表型社区。 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、炎症、代谢物、脂质体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；(2)GMC将作为STAC 提供甲基化、转录组(血液、脑、脑脊液)、ATAC-Seq、单细胞组学数据和 用于产生可用的IPSC和有机化合物；(3)GMC将开发和分享创新的遗传和多组体 关联性分析方法，特别是在大家庭中使用；(4)GMC将促进与 阿尔茨海默病遗传学联合会(ADGC)、阿尔茨海默病国际基因组学协会 IGAP项目，基因组流行病学和跨基因组学心脏和衰老研究队列(CHARE) 精准医学(TOPMed)；(V)GMC教员和资源将支持研究教育核心在 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训练有素。

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.