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

基本信息

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
项目类别：
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&apos 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

项目摘要

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 发现阶段将鉴定假定的新 AD 基因/变体。然而，为了令人信服地建立新的迟发性 AD (LOAD) 基因座，复制至关重要，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 资助者共同决定 http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-16-002.html。在这里，我们提出了一种具有成本效益的策略，利用通过心脏和衰老基因组流行病学研究队列 (CHARGE) 及其大型合作者网络获得的表型、内表型、基因组和多维组学数据。在目标 1 中，我们将对发现和复制阶段的表型和遗传数据进行协调，以验证变异和基因水平 AD 关联，并发现新基因，补充 U54 的工作。样本将从非洲、西班牙裔、亚洲和欧洲血统的社区队列中抽取（> 15,000 例病例和 100,000 名对照，其中 60,000 名以上年龄在 65 岁以上）。四分之一的样本已经有可用的序列数据（全外显子组、全基因组）；其他人将有资格接受 NHGRI 复制测序。全基因组阵列数据超过 65,000 个，我们建议使用 Illumina 多种族基因型阵列 (MEGA) 芯片（具有定制 AD 内容），对另外约 10,000 个表型丰富的样本进行基因分型，这些样本均选择为非欧洲或欧洲样本但采用独特的措施（例如淀粉样蛋白 PET 扫描）。我们将整合阵列和序列数据，使用代表研究样本祖先多样性的改进参考面板对常见和适度罕见的变异进行插补。在目标 2 中，我们将利用多种族和混合样本中的精细群体结构来验证和精细绘制发现阶段基因座，并通过跨种族荟萃分析和混合作图来识别新的 AD 基因座。此外，我们将通过研究先前一致的和新的、敏感的内表型来确定新的 AD 相关关联并询问生物学途径，包括（1）脑 MRI：海马体积、白质微结构损伤和皮质萎缩的“AD 特征”模式； (2)认知：一般认知表现和言语记忆； (3)生物标志物：PET淀粉样蛋白负荷和循环β-淀粉样蛋白水平。在目标 3 中，我们将获得对生物学的更多见解，并优先考虑用于实验后续和药物开发的基因座。具体来说，我们将利用生物信息学工具和“组学”数据，包括来自 CHARGE 的可用 DNA 甲基化、基因表达、miRNA 和代谢组学，并通过 Accelerated Medicine Partnerships-AD (AMP-AD) 项目来创建和验证 AD 特异性组合注释最后，我们将利用依赖性缺失工具（AD-CADD）解析最有希望的基因座，以使用果蝇敲低模型进行进一步的功能探索。