Next generation functional genomics of hematology traits

项目摘要 该项目的总体目标是解决生物学解释、功能性解释和生物学解释方面的几个主要挑战。 验证和临床翻译的遗传关联结果的定量红细胞性状和非 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 和计算工具，以极大的人类多种族人口为基础的数据集， 在数千个具有红细胞性状（血红蛋白、血细胞比容、RBC计数、MCV、MCH、MCHC， 红细胞分布宽度（RDW）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），以提供更新的分析，发现， 与红细胞相关的常见、低频率和罕见遗传变异的结果解读 计数和指数。在目的2中，验证新的红细胞表型相关基因组基因座和遗传学特征。 变异将通过独立数据集的插补和重复组合发生（使用TOPMed WGS作为插补参考组），和/或从头基因分型或所选表型的序列分析。 样本或谱系。我们还将为新的和 现有的红细胞性状相关的变异和基因，重点是新的血细胞谱系特异性 表观基因组学、转录组学和3D基因组学资源，包括通过TOPMed获得的资源 蓝图项目。在目标3中，我们将对选定的非编码基因进行功能性、基于细胞的分析。 在目标1和2中确定的基因组位点/变体（每年约50个）（特别是那些改变典型转录的基因组位点/变体 因子基序，并通过PheWAS或与表型极端的共分离证明临床影响， 谱系），利用大规模平行报告基因测定（MPRA）和CRISPR/Cas9基因组测序的组合， 干扰以询问非编码遗传变异，从而提供全面的和预测的 评估监管非编码变异和功能。我们将传播所有的基因组，注释， 源自目标1、2和3的功能信息，以确保将知识传播到临床和 科学界，用于发现，精细定位和调查红细胞的致病基因 性状和血液系统疾病。

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.