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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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.
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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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.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–17 and Supplementary Note
Summary statistics and information for all fine-mapped variants with PP > 0.001
Summary of top fine-mapped configurations in each region
Summary of fine-mapped coding variants
Summary statistics for bulk ATAC-seq libraries
Summary of motif-disrupting variants occupied by corresponding transcription factors
Summary of putative gene targets for variants mapping to PCHi-C interactions
Summary of putative gene targets for variants mapping to ATAC–RNA correlations
Fine-mapped variants with PP > 0.05 identified in the same 3-Mb region
Pleiotropic variants (PP > 0.01) for blood cell count traits
g-chromVAR results for 39 predominantly immune-related disorders previously fine-mapped with PICS to 18 chromatin accessibility profiles
Application of g-chromVAR to DNase I hypersensitivity data for 53 tissues from Roadmap Epigenomics
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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