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

Item Type:Article
Title:Interrogation of human hematopoiesis at single-cell and single-variant resolution
Creators Name:Ulirsch, J.C. and Lareau, C.A. and Bao, E.L. and Ludwig, L.S. and Guo, M.H. and Benner, C. and Satpathy, A.T. and Kartha, V.K. and Salem, R.M. and Hirschhorn, J.N. and Finucane, H.K. and Aryee, M.J. and Buenrostro, J.D. and Sankaran, V.G.
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.
Keywords:Cell Lineage, Chromatin, Chromosome Mapping, Epigenomics, Genome-Wide Association Study, Hematopoiesis, Linkage Disequilibrium, Nucleic Acid Regulatory Sequences, Phenotype, Quantitative Trait Loci, Single Nucleotide Polymorphism
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:683-693
Date:April 2019
Official Publication:https://doi.org/10.1038/s41588-019-0362-6
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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