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Nat Genet. 2019 Apr;51(4):683-693. doi: 10.1038/s41588-019-0362-6. Epub 2019 Mar 11.

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

Ulirsch JC1,2,3,4, Lareau CA1,2,3,4,5, Bao EL1,2,3,6, Ludwig LS1,2,3, Guo MH3,7,8,9, Benner C10,11, Satpathy AT12, Kartha VK3,13, Salem RM3,7,8,9, Hirschhorn JN3,7,8,9, Finucane HK3,14, Aryee MJ3,5,15, Buenrostro JD16,17, Sankaran VG18,19,20,21.

Author information

1
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
5
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
6
Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, USA.
7
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
8
Department of Genetics, Harvard Medical School, Boston, MA, USA.
9
Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
10
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
11
Department of Public Health, University of Helsinki, Helsinki, Finland.
12
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
13
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
14
Schmidt Fellows Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
15
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
16
Broad Institute of MIT and Harvard, Cambridge, MA, USA. jason_buenrostro@harvard.edu.
17
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. jason_buenrostro@harvard.edu.
18
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. sankaran@broadinstitute.org.
19
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. sankaran@broadinstitute.org.
20
Broad Institute of MIT and Harvard, Cambridge, MA, USA. sankaran@broadinstitute.org.
21
Harvard Stem Cell Institute, Cambridge, MA, USA. sankaran@broadinstitute.org.

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.

PMID:
30858613
PMCID:
PMC6441389
[Available on 2019-09-11]
DOI:
10.1038/s41588-019-0362-6
[Indexed for MEDLINE]

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