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Interrogation of human hematopoiesis at single-cell and single-variant resolution

Nature Genetics volume 51, pages 683–693 (2019)Cite this article

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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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Fig. 1: Overview of hematopoiesis, UKB GWAS, and fine-mapping.
Fig. 2: Mechanisms of core gene regulation in blood production.
Fig. 3: Characterization and validation of the CCND3 and AK3 regions with multiple causal variants.
Fig. 4: Dissecting the mechanisms of pleiotropic variants across multiple blood cell lineages.
Fig. 5: Overview of g-chromVAR and application to hematopoietic cell types.
Fig. 6: Application of g-chromVAR to single-cell chromatin accessibility data.

Code availability

g-chromVAR is available as an open-source R package distributed freely at http://caleblareau.github.io/gchromVAR. All code required to reproduce the results discussed herein has been made available at http://github.com/caleblareau/singlecell_bloodtraits.

Data availability

All processed data are available on GitHub (https://github.com/caleblareau/singlecell_bloodtraits/). ATAC-seq profiles are available from the Gene Expression Omnibus (GEO) under accession GSE119453 and from the Sequence Read Archive (SRA) under accession PRJNA491478.

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Acknowledgements

We thank members of the Sankaran, Buenrostro, and Finucane laboratories for their helpful discussions. This work was supported by National Institutes of Health (NIH) grants R01 DK103794 and R33 HL120791 (to V.G.S.), by the New York Stem Cell Foundation (NYSCF; to V.G.S.), and by the Harvard Society and Broad Institute Fellows programs (to J.D.B.). J.C.U. is supported by an NIH training grant (5T32 GM007226-43). C.A.L. is supported by an NIH predoctoral fellowship (F31 CA232670). E.L.B. is supported by the Howard Hughes Medical Institute Medical Research Fellows Program. V.G.S. is supported as an NYSCF-Robertson Investigator. This research was conducted by using the UK Biobank resource under projects 11898 and 31063.

Author information

Author notes

  1. These authors contributed equally: Jacob C. Ulirsch, Caleb A. Lareau, Erik L. Bao.

Authors and Affiliations

  1. Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Jacob C. Ulirsch, Caleb A. Lareau, Erik L. Bao, Leif S. Ludwig & Vijay G. Sankaran

  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Jacob C. Ulirsch, Caleb A. Lareau, Erik L. Bao, Leif S. Ludwig & Vijay G. Sankaran

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jacob C. Ulirsch, Caleb A. Lareau, Erik L. Bao, Leif S. Ludwig, Michael H. Guo, Vinay K. Kartha, Rany M. Salem, Joel N. Hirschhorn, Hilary K. Finucane, Martin J. Aryee, Jason D. Buenrostro & Vijay G. Sankaran

  4. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA

    Jacob C. Ulirsch & Caleb A. Lareau

  5. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Caleb A. Lareau & Martin J. Aryee

  6. Harvard–MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, USA

    Erik L. Bao

  7. Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Michael H. Guo, Rany M. Salem & Joel N. Hirschhorn

  8. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Michael H. Guo, Rany M. Salem & Joel N. Hirschhorn

  9. Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA

    Michael H. Guo, Rany M. Salem & Joel N. Hirschhorn

  10. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    Christian Benner

  11. Department of Public Health, University of Helsinki, Helsinki, Finland

    Christian Benner

  12. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    Ansuman T. Satpathy

  13. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA

    Vinay K. Kartha & Jason D. Buenrostro

  14. Schmidt Fellows Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Hilary K. Finucane

  15. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Martin J. Aryee

  16. Harvard Stem Cell Institute, Cambridge, MA, USA

    Vijay G. Sankaran

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Contributions

J.C.U., C.A.L., E.L.B., M.J.A., J.D.B., and V.G.S. designed the study. J.C.U., C.A.L., E.L.B., and M.H.G. analyzed data. L.S.L. performed experiments. C.B., A.T.S., V.K.K., R.M.S., and J.N.H. contributed ideas and insights. H.K.F., M.J.A., J.D.B., and V.G.S. supervised this work. J.D.B. and V.G.S. obtained funding. J.C.U., C.A.L., E.L.B., and V.G.S. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Jason D. Buenrostro or Vijay G. Sankaran.

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The authors declare no competing interests.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–17 and Supplementary Note

Reporting Summary

Supplementary Table 1

Summary statistics and information for all fine-mapped variants with PP > 0.001

Supplementary Table 2

Summary of top fine-mapped configurations in each region

Supplementary Table 3

Summary of fine-mapped coding variants

Supplementary Table 4

Summary statistics for bulk ATAC-seq libraries

Supplementary Table 5

Summary of motif-disrupting variants occupied by corresponding transcription factors

Supplementary Table 6

Summary of putative gene targets for variants mapping to PCHi-C interactions

Supplementary Table 7

Summary of putative gene targets for variants mapping to ATAC–RNA correlations

Supplementary Table 8

Fine-mapped variants with PP > 0.05 identified in the same 3-Mb region

Supplementary Table 9

Pleiotropic variants (PP > 0.01) for blood cell count traits

Supplementary Table 10

g-chromVAR results for 39 predominantly immune-related disorders previously fine-mapped with PICS to 18 chromatin accessibility profiles

Supplementary Table 11

Application of g-chromVAR to DNase I hypersensitivity data for 53 tissues from Roadmap Epigenomics

Supplementary Table 12

Top differentially enriched transcription factors between CMP and MEP subclusters

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Ulirsch, J.C., Lareau, C.A., Bao, E.L. et al. Interrogation of human hematopoiesis at single-cell and single-variant resolution. Nat Genet 51, 683–693 (2019). https://doi.org/10.1038/s41588-019-0362-6

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