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

描述（由申请人提供）：ADSP发现阶段将确定假定的新的AD基因/变体。然而，为了令人信服地建立新的晚发性AD （LOAD）基因座，复制是必不可少的，NHGRI将资助1.4万至3万人的复制测序。样本选择和分析策略将由ADSP指导委员会与RFA的获奖者一起确定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，利用基因组流行病学心脏与衰老研究队列（CHARGE）及其庞大的合作者网络提供的表型、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的AD关联，以及新基因的发现，补充U54的工作。样本将从以社区为基础的非洲人、西班牙人、亚洲人和欧洲人的队列中抽取（15,000例病例和100,000例对照，其中60,000例年龄在65岁以上）。四分之一的样本已经有序列数据（全外显子组，全基因组）可用；其余的将有资格进行NHGRI复制测序。基因组范围内的阵列数据可在bbb65,000中获得，我们建议使用Illumina多种族基因型阵列（MEGA）芯片，定制AD内容，对额外的~10,000个丰富表型的样本进行基因型分析，选择非欧洲或欧洲但具有独特测量方法（例如，淀粉样蛋白PET扫描）。我们将整合阵列和序列数据，使用改进的代表研究样本祖先多样性的参考面板，对常见和中等罕见变异进行代入。在目标2中，我们将利用多种族和混合样本的精细尺度人口结构来验证和精细绘制发现阶段的基因座，并通过跨种族的荟萃分析和混合绘图来识别新的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，包括(1)脑MRI：海马体积，白质微结构损伤和皮层萎缩的“AD特征”模式，确定新的AD相关关联和询问生物学途径；(2)认知：一般认知表现和言语记忆；(3)生物标志物：PET淀粉样蛋白负荷和循环β -淀粉样蛋白水平。在Aim 3中，我们将获得更多的生物学见解，并优先考虑实验后续和药物开发的基因座。具体而言，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，并通过加速医学合作伙伴关系- ad （AMP-AD）项目创建和验证ad特异性联合注释依赖消耗工具（AD-CADD），最后，我们将分析最有希望的位点，以进一步使用果蝇敲低模型进行功能探索。

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.