Interrogation of human hematopoiesis at single-cell and single-variant resolution
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Abstract
Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. For regulatory variants, we explore patterns of developmental enhancer activity, predict molecular mechanisms, and identify likely target genes. In several instances, we localize multiple independent variants to the same regulatory element or gene. We further observe that variants with pleiotropic effects preferentially act in common progenitor populations to direct the production of distinct lineages. Finally, we leverage fine-mapped variants in conjunction with continuous epigenomic annotations to identify trait-cell type enrichments within closely related populations and in single cells. Our study provides a comprehensive framework for single-variant and single-cell analyses of genetic associations.
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These associations suggest that human variation may modulate regulatory mechanisms across the full hematopoietic hierarchy.
“These associations suggest that human variation may modulate regulatory mechanisms across the full hematopoietic hierarchy (Figure 1) (Ulirsch et al., 2019).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Ulirsch et al., 2019
The ability to fine-map variants associated with blood cell traits and overlap these variants with accessible chromatin in hematopoietic progenitors has provided unprecedented insight into how genetic variation can influence a range of cell states in hematopoiesis.
“In addition, the ability to fine-map variants associated with blood cell traits and overlap these variants with accessible chromatin in hematopoietic progenitors has provided unprecedented insight into how genetic variation can influence a range of cell states in hematopoiesis (Ulirsch et al., 2019; Vuckovic et al., 2020).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Ulirsch et al., 2019
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- Authors
- Ulirsch, J. C., Lareau, C. A., Bao, E. L., Ludwig, L. S., Guo, M. H., Benner, C., Satpathy, A. T., Kartha, V. K., Salem, R. M., Hirschhorn, J. N., Finucane, H. K., Aryee, M. J., Buenrostro, J. D., & Sankaran, V. G.
- Affiliations
- Broad Institute (US)
- University of Helsinki (FI)
- Stanford Medicine (US)
- Corresponding author
- Buenrostro, Jason D.
- Sankaran, Vijay G.
- ORCID
- Venue
- Nature Genetics
- Published
- 2019-03-11
- Volume
- 51
- Issue
- 4
- Pages
- 683-693
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6441389
- OpenAlex
- W2953047957
- Cited by
- 208
- References
- 89
- Citations by year
- 2026: 26 · 2025: 25 · 2024: 26 · 2023: 19 · 2022: 28 · 2021: 25 · 2020: 34 · 2019: 21 · 2018: 3
- FWCI
- 16.37
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Broad Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R33HL120791)
- National Human Genome Research Institute (K99HG012579)
- National Cancer Institute (F31CA232670)
- National Institute of General Medical Sciences (T32GM007226)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075787, R01DK103794)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- hematopoiesis, blood cell traits, genetic fine-mapping, causal variants, regulatory variants, enhancer activity, hematopoietic progenitor cells, chromatin accessibility, pleiotropy, lineage specification, epigenomics, single-cell analysis, UK Biobank
- MeSH terms
- Chromatin, Chromosome Mapping, Hematopoiesis, Humans, Phenotype, Regulatory Sequences, Nucleic Acid, Linkage Disequilibrium, Cell Lineage, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Epigenomics
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