ArticleProceedings of the National Academy of Sciences of the United States of America2017
Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 66 citations in OpenAlex.
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- Genome-wide discovery for biomarkers using quantile regression at biobank scale.Nature communications · 2024Article
- Ribosomal DNA copy number variation associates with hematological profiles and renal function in the UK Biobank.Cell genomics · 2024Article
- The Role of Rab GTPases in the development of genetic and malignant diseases.Molecular and cellular biochemistry · 2024Review
- Novel insights into the ontogeny of basophils.Frontiers in allergy · 2024Review
- Cross-tissue patterns of DNA hypomethylation reveal genetically distinct histories of cell development.BMC genomics · 2023Article
- Article
- Hacking hematopoiesis - emerging tools for examining variant effects.Disease models & mechanisms · 2023Article
- Article
- Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis.American journal of human genetics · 2021Article
- Common variants in signaling transcription-factor-binding sites drive phenotypic variability in red blood cell traits.Nature genetics · 2020Article
- Review
- In The Blood: Connecting Variant to Function In Human Hematopoiesis.Trends in genetics : TIG · 2020Review
- Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci.Nature genetics · 2020Article
- Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis.eLife · 2019Article
- Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records.European journal of human genetics : EJHG · 2019Article
- Biological relevance of computationally predicted pathogenicity of noncoding variants.Nature communications · 2019Article
- Article
- CRISPR-based strategies for studying regulatory elements and chromatin structure in mammalian gene control.Mammalian genome : official journal of the International Mammalian Genome Society · 2018Review
Corrections and comments
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Authors and funding
22 authors at 8 institutions in 4 countries.
Funding
Abstract
Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.
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