Document text
Principal Investigator: ALEXANDER P REINER
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $761,033
Funding agency: National Heart Lung and Blood Institute
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. We seek to significantly advance the work that we have
done over the current funding cycle to define how genetic variants can impact erythrocyte (red blood cell) traits
and to functionally define mechanisms through which these variants act. In Aim 1, we will apply state-of-the-art
statistical genomic and computational tools to extremely large human multi-ethnic datasets containing nearly 1
million individuals with red blood cell traits (hemoglobin, hematocrit, RBC count, MCV, MCH, MCHC, red cell
distribution width or RDW) and whole genome sequence (WGS) or exome sequence data (the NHLBI TOPMed
WGS project, UK Biobank, All of Us, and deCODE) to provide updated analysis, discovery, and interpretation of
results, particularly for rare and ancestry-specific genetic variants associated with red blood cell counts and
indices. We will include analysis of genomic regions missed by prior GWAS efforts such as large structural
variants, variants on the X chromosome, and mitochondrial DNA copy number. Validation of new red blood cell
phenotype-associated genomic loci and genetic variants will occur through imputation and replication in
independent data sets using TOPMed WGS as imputation reference panel. We will also continue to provide
functional annotation, fine-mapping, and prioritization for new and existing red blood cell trait-associated variants
and genes, with an emphasis on utilization of newer multi-omic data sets derived from African and Hispanic
individuals that are becoming available through the TOPMed project. In Aim 2, we will assess the contribution
of polygenic variation (across the entire allele frequency spectrum) as phenotypic modifiers of red cell disorders
such as anemia and erythrocytosis, phenotypic expressivity of high-impact Mendelian red cell disorders, and the
contribution of red cell polygenicity to other complex disorders such as venous thromboembolic disease, stroke,
and COVID-19 disease severity. In Aim 3, building on previous integrative genomic and functional analyses to
define relevant hematopoietic cell states and mechanisms, we will develop comprehensive maps of how genetic
variation associated with red blood cell traits can impact human hematopoiesis using emerging single-cell
epigenomic chromatin accessibility and RNA sequencing atlases to provide 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.
Terms: <Achievement><Achievement Attainment><Address><Admixture><African><African American><African ancestry><African descent><Afro American><Afroamerican><Allele Frequency><Anemia><Apoplexy><Architecture><Asian Americans><Asian ancestry><Asian descent><Atlases><Award><Base Sequence><Biological><Biology><Blood><Blood Cells><Blood Diseases><Blood Reticuloendothelial System><Blood erythrocyte><Brain Vascular Accident><COVID disease severity><COVID severity><COVID-19 disease severity><COVID-19 infection><COVID-19 predisposition><COVID-19 severity><COVID-19 susceptibility><COVID-19 virus infection><COVID-19 vulnerability><COVID19 disease severity><COVID19 infection><COVID19 severity><Cell Body><Cell Lineage><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chromatin><Chromosome Mapping><Clinical><Communities><Complex><Computational toolkit><Copy Number Polymorphism><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><DNA copy number><Data><Data Set><Disease><Disorder><East Asian><Engineering / Architecture><Ensure><Erythrocyte Count><Erythrocyte Measurement><Erythrocyte Number><Erythrocytes><Erythrocytic><Erythrocytoses><European><Frequencies><Functional RNA><Funding><GWA study><GWAS><Gene Frequency><Gene Localization><Gene Mapping><Gene Mapping Genetics><Gene variant><Genes><Genetic><Genetic Diversity><Genetic Risk><Genetic Variation><Genome><Genomic Segment><Genomics><Goals><Grant><Hct><Hematocrit><Hematocrit procedure><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hematology><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Hemoglobin><Heterogeneity><Hispanic><Hispanic Populations><Hispanic group><Hispanic individual><Hispanic people><Hispanics><Human><Individual><Investigation><Joints><Knowledge><Latino Population><Latino group><Latino individual><Latino people><Latinos><Linkage Mapping><Maps><Marrow erythrocyte><Methods><Minor><Mitochondria><Mitochondrial DNA><Modeling><Modern Man><Multiomic Data><NHLBI><National Heart, Lung, and Blood Institute><Native Americans><Non-Coding><Non-Coding RNA><Non-Malignant><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleotide Sequence><Outcome><Packed Erythrocyte Volume><Packed Red-Cell Volume><Penetrance><Peripheral Blood Cell><Phase><Phenotype><Polygenic Characters><Polygenic Inheritances><Polygenic Traits><Population><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Production><Public Health><RNA Seq><RNA sequencing><RNAseq><Red Blood Cell Count><Red Blood Cells><Red Cell><Research><Research Resources><Resources><Risk><Risk Factors><SARS-CoV-2 disease severity><SARS-CoV-2 infection><SARS-CoV-2 predisposition><SARS-CoV-2 severity><SARS-CoV-2 susceptibility><SARS-CoV-2 vulnerability><SARS-CoV2 infection><Sample Size><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Single Base Polymorphism><Single Nucleotide Polymorphism><Stroke><TOPMed><Total Human and Non-Human Gene Mapping><Trans-Omics for Precision Medicine><Untranslated RNA><Update><Validation><Variant><Variation><Venous><Width><Work><X Chromosome><allele variant><allelic frequency><allelic variant><biobank><biologic><biorepository><blood cell formation><blood corpuscles><blood disorder><brain attack><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cerebral vascular accident><cerebrovascular accident><clinical translation><clinically translatable><computational toolbox><computational tools><computational toolset><computerized tools><copy number variant><copy number variation><coronavirus disease 2019 disease severity><coronavirus disease 2019 infection><coronavirus disease 2019 severity><coronavirus disease severity><entire genome><epigenomics><ethnic diversity><ethnically diverse><exome><exomes><full genome><functional genomics><gene locus><genetic architecture><genetic association><genetic locus><genetic mapping><genetic variant><genome resource><genome segment><genome wide analysis><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome wide studies><genome-wide analysis><genome-wide identification><genomewide association scan><genomewide association studies><genomewide association study><genomic data resource><genomic location><genomic locus><genomic region><genomic resource><genomic sequencing resource><genomic tools><genomic variant><global health><health equity><hemopoietic><human disease><improved><indexing><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insight><mitochondrial><mtDNA><multi-ethnic><multiethnic><multiple omic data><next generation><noncoding><nonmalignant><novel><nucleic acid sequence><pleiotropic effect><pleiotropism><pleiotropy><population based><predisposed to Coronavirus disease 2019><rare allele><rare mutation><rare variant><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 severity><single cell genomics><single nucleotide variant><stroked><strokes><success><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><trait><transcriptome sequencing><transcriptomic sequencing><validations><vulnerable to COVID-19><vulnerable to Coronavirus disease 2019><vulnerable to SARS-CoV-2><vulnerable to Severe acute respiratory syndrome coronavirus 2><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>