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

Incomplete annotation of cell-to-cell state variation and widespread linkage disequilibrium in the human genome represent significant challenges to elucidating mechanisms of trait-associated genetic variation. Here, using data from the UK Biobank, we perform genetic fine-mapping for 16 blood cell traits to quantify posterior probabilities of association while allowing for multiple independent signals per region. We observe an enrichment of fine-mapped variants in genes encoding for trait-relevant biological pathways and in accessible chromatin of lineage-committed hematopoietic progenitor cells. For fine-mapped regulatory variants, we gain insights into patterns of developmental enhancer activity and identify putative molecular mechanisms, including several regulatory elements that contain independent functional variants, as well as target genes. Across diverse blood cell lineages, we observe 172 fine-mapped pleiotropic variants, finding that ~90% of these tune the production of distinct lineages in consistent directions, whereas ~10% favor the production of a single lineage at the expense of others. Finally, we develop a novel analytic framework that takes advantage of fine-mapping to identify “core gene” cell type enrichments and show that this approach uniquely resolves relevant cell types within closely related populations. Applying our approach to single cell chromatin accessibility data, we discover significant heterogeneity within classically defined multipotential progenitor populations. In total, our study provides an analytic framework for single-variant and single-cell analyses and represents one of the most comprehensive maps of variant to function to date. Overall design: Biological replicates (2 per population) were processed across 1 biological donor for bulk ATAC-seq