ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems

通过内表型、组学对多种族队列进行 ADSP 随访

• 批准号: 9078875
• 负责人: MYRIAM FORNAGE
• 金额: $ 63.44万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9078875
• 关键词: African; African American; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Architecture; Asians; Base Sequence; Bioinformatics; Biological; Biological Markers; Biological Models; Biological Process; Biology; Brain; Clinical; Cognition; Collaborations; Collection; Communities; Custom; DNA Methylation; Data; Data Discovery; Databases; Drosophila genus; Elderly; Epidemiology; Epigenetic Process; Ethnic group; European; Family; Funding; Gene Expression; Genes; Genetic; Genetic Variation; Genomic approach; Genomics; Genotype; Goals; Grant; Health; Heart; Hippocampus (Brain); Hispanics; Human; Individual; Injury; Joints; Laboratories; Late Onset Alzheimer Disease; Location; Magnetic Resonance Imaging; Maps; Measures; Medicine; Memory; Meta-Analysis; Methods; MicroRNAs; Mining; Minority; Modeling; National Human Genome Research Institute; Nature; Participant; Pathway interactions; Pattern; Persons; Phase; Phenotype; Population; Positron-Emission Tomography; Process; Race; Research; Research Design; Research Personnel; Resources; Risk; Sampling; Sampling Studies; Structure; Testing; Validation; Variant; Work; admixture mapping; base; case control; cerebral atrophy; cognitive function; cognitive performance; cohort; cost effective; database of Genotypes and Phenotypes; drug development; endophenotype; ethnic diversity; exome; exome sequencing; follow-up; functional genomics; gene discovery; genetic association; genetic variant; genome wide association study; genome-wide; genomic data; improved; insight; knock-down; metabolomics; new therapeutic target; next generation sequencing; novel; phenotypic data; rare variant; targeted sequencing; tool; trait; web site; white matter; whole genome

DESCRIPTION (provided by applicant): The ADSP discovery phase will identify putative novel AD genes/variants. Nevertheless, to convincingly establish new late-onset AD (LOAD) loci, replication is essential and NHGRI will fund replication sequencing in 14,000 to 30,000 persons. Sample selection and analytical strategies will be determined by the ADSP Steering Committee in conjunction with grant awardees of RFA http://grants.nih.gov/grants/guide/rfa-files/RFA- AG-16-002.html. Here, we propose a cost-effective strategy to leverage phenotypic, endophenotypic, genomic and multi-dimensional omics data available through the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and its large network of collaborators. In Aim 1, we will perform harmonization of phenotypic and genetic data from discovery and replication phases for validation of variant- and gene-level AD associations, and for novel gene discovery, supplementing U54 efforts. Samples will be drawn from community-based cohorts of African, Hispanic, Asian, and European ancestry (>15,000 cases & 100,000 controls, of whom >60,000 are over age 65). One quarter of the sample already has sequence data (whole exome, whole genome) available; the others will be eligible for the NHGRI replication sequencing. Genome- wide array data are available in >65,000 and we propose to use the Illumina Multi-Ethnic Genotype Array (MEGA) chip, with custom AD content, to genotype an additional ~10,000 richly phenotyped samples, selected for being non-European or European but with unique measures (e.g., with amyloid PET scans). We will integrate array- and sequence data to perform imputation of common and moderately rare variants using improved reference panels that represent the ancestral diversity of the study samples. In Aim 2, we will leverage fine-scale population structure in multi-ethnic and admixed samples to validate and fine-map discovery phase loci, and also identify novel AD loci through trans-ethnic meta-analyses and admixture mapping. In addition, we will identify novel AD-relevant associations and interrogate biological pathways by studying previously-harmonized and new, sensitive endophenotypes including (1) Brain MRI: hippocampal volumes, white matter microstructural injuries and `AD signature' patterns of cortical atrophy; (2) Cognition: general cognitive performance and verbal memory; (3) Biomarker: PET amyloid burden and circulating beta- amyloid levels. In Aim 3, we will gain additional insight into biology and prioritize loci for experimental follow-up and drug development. Specifically, we will utilize bioinformatic tools and "omics" data, including available DNA methylation, gene expression, miRNA and metabolomics from CHARGE and through the Accelerated Medicine Partnerships-AD (AMP-AD) project to create and validate an AD-specific Combined Annotation Dependent Depletion tool (AD-CADD), finally, we will parse the most promising loci for further functional exploration using Drosophila knockdown models.

描述（由申请人提供）：ADSP发现阶段将识别推定的新型AD基因/变体。但是，要令人信服地建立新的后期广告（负载）基因座，复制是必不可少的，NHGRI将资助14,000至30,000人的复制测序。样本选择和分析策略将由ADSP指导委员会与RFA http://grants.nih.gov/grants/guide/rfa-files/rfa-files/rfa- ag-16-002.html一起确定。在这里，我们提出了一种具有成本效益的策略，以利用表型，内型，基因组和多维的OMICS数据，可通过共同研究获得基因组流行病学（CHALL）的心脏和衰老研究及其大型合作者网络。在AIM 1中，我们将从发现和复制阶段进行表型和遗传数据的统一，以验证变异和基因级AD关联，并为新颖的基因发现，补充U54的努力。样本将来自基于社区的非洲，西班牙裔，亚洲和欧洲血统的同类（> 15,000例案例和100,000个对照组，其中> 60,000年龄在65岁以上）。四分之一的样本已经具有可用的序列数据（整个外显子，全基因组）。其他将有资格参加NHGRI复制测序。基因组 - 宽阵列数据可在> 65,000中获得，我们建议使用具有自定义AD含量的Illumina多种族基因型阵列（Mega）芯片，以提供约10,000种〜10,000个较丰富的表型样品，以非欧洲或欧洲为非欧洲，但具有独特的指标（例如，具有淀粉样的PET扫描）。我们将使用改进的参考面板来集成阵列和序列数据，以执行常见和中等稀有变体的插补，这些变体代表了研究样本的祖先多样性。在AIM 2中，我们将利用多种族和混合样品中的细尺度种群结构来验证和精细地图发现阶段基因座，并通过跨种族的荟萃分析和混合映射来识别新颖的AD基因座。此外，我们将通过研究先前的疾病和新的，敏感的内表型，包括（1）脑MRI：海马体积，白质微结构损伤和“ AD AD SIGNATALION”模式，来确定新型的与AD相关的关联并询问生物学途径； （2）认知：一般认知表现和言语记忆； （3）生物标志物：宠物淀粉样蛋白负担和循环β-淀粉样蛋白水平。在AIM 3中，我们将获得对生物学的更多见解，并确定基因座的实验随访和药物开发。具体而言，我们将利用生物信息学工具和“ OMICS”数据，包括可用的DNA甲基化，基因表达，miRNA和通过电荷和通过加速的医学合作伙伴关系（AMP-AD）项目来创建和验证广告特定的组合依赖的DEPLETENT DEPLETENT工具（AD-CADD），最终将启用，我们最需要的是，我们将建立和验证广告，以创建和验物敲低模型。