Next generation functional genomics of hematology traits

项目总结 这个项目的总体目标是解决生物学解释、功能和功能的几个主要挑战 红细胞数量性状和非数量性状的遗传关联结果的验证和临床翻译 后基因组时代的恶性血细胞疾病。在目标1中，我们将应用最先进的统计基因组学 和计算工具，用于包含数百个基于多种族人口的超大人类数据集 数以千计具有红细胞特征(血红蛋白、红细胞压积、RBC计数、MCV、MCH、MCHC、 红细胞分布宽度)和全基因组序列(WGS)数据(NHLBI TOPMed WGS项目) 或Gwas数据(血细胞联盟或BCX和英国生物库)，以提供最新的分析、发现和 与红细胞相关的常见、低频和罕见遗传变异的结果解释 计数和索引。在目标2中，验证新的与红细胞表型相关的基因组座位和基因 变异将通过在独立数据集中(使用TOPMed)中的推算和复制的组合来发生 WGS作为归因参考小组)，和/或选定表型的从头基因分型或序列分析 样本或家谱。我们还将为新的和 现有的与红细胞特性相关的变体和基因，重点是新的血细胞谱系特异性 表观基因组、转录组和3D基因组资源，包括可通过TOPMed获得的资源 和蓝图项目。在目标3中，我们将对选定的非编码进行基于细胞的功能性分析 目标1和目标2中确定的基因组座位/变异(每年~50个)(特别是那些改变规范转录的基因 因子基序和通过Phewas或与表型极端的共分离显示临床影响 家系)使用大规模平行报告分析(MPRA)和CRISPR/Cas9基因组相结合 干扰以询问非编码遗传变异，从而提供全面和预测性 对调节性非编码变异和功能的评估。我们将传播所有基因组、注释和 源自目标1、2和3的功能信息，以确保将知识传播给临床和 科学界，用于发现、精细绘制和研究构成红细胞的因果基因 特征和血液系统疾病。

PROJECT SUMMARY The over-arching goal of this project is to address several major challenges to biologic interpretation, functional validation, and clinical translation of genetic association findings for quantitative red blood cell traits and non- malignant blood cell disorders in the post-genomic era. In Aim 1, we will apply state-of-the-art statistical genomic and computational tools to extremely large human multi-ethnic population-based datasets containing hundreds of thousands of individuals with red blood cell traits (hemoglobin, hematocrit, RBC count, MCV, MCH, MCHC, red cell distribution width or RDW) and whole genome sequence (WGS) data (the NHLBI TOPMed WGS project) or GWAS data (Blood Cell Consortium or BCX and UK Biobank) to provide updated analysis, discovery, and interpretation of results for common, low-frequency, and rare genetic variants associated with red blood cell counts and indices. In Aim 2, validation of new red blood cell phenotype-associated genomic loci and genetic variants will occur through a combination of imputation and replication in independent data sets (using TOPMed WGS as imputation reference panel), and/or de novo genotyping or sequence analysis of selected phenotypic samples or pedigrees. We will also provide functional annotation, fine-mapping, and prioritization for new and existing red blood cell trait-associated variants and genes, with an emphasis on new blood cell lineage-specific epigenomic, transcriptomic, and 3D genomic resources, including those becoming available through TOPMed and BLUEPRINT projects. In Aim 3, we will perform functional, cell-based analyses of selected non-coding genomic loci/ variants (~50 per year) identified in Aims 1 and 2 (particularly those that alter canonical transcription factor motifs and demonstrate clinical impact through PheWAS or co-segregation with phenotypic extremes in pedigrees) utilizing a combination of massively parallel reporter assays (MPRA) and CRISPR/Cas9 genomic perturbation to interrogate non-coding genetic variation and thereby provide comprehensive and predictive assessments of regulatory non-coding variation and function. We will disseminate all genomic, annotation, and functional information derived from Aims 1, 2, and 3 to ensure knowledge dissemination to the clinical and scientific community, for discovery, fine-mapping, and investigation of causal genes that underlie red blood cell traits and hematological disorders.