RT Journal Article SR Electronic T1 Interrogation of human hematopoiesis at single-cell and single-variant resolution JF bioRxiv FD Cold Spring Harbor Laboratory SP 255224 DO 10.1101/255224 A1 Caleb A. Lareau A1 Jacob C. Ulirsch A1 Erik L. Bao A1 Leif S. Ludwig A1 Michael H. Guo A1 Christian Benner A1 Ansuman T. Satpathy A1 Rany Salem A1 Joel N. Hirschhorn A1 Hilary K. Finucane A1 Martin J. Aryee A1 Jason D. Buenrostro A1 Vijay G. Sankaran YR 2018 UL http://biorxiv.org/content/early/2018/01/28/255224.abstract AB Incomplete annotation of cell-to-cell state variance 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 accessible chromatin of lineage-committed hematopoietic progenitor cells. Further, we develop a novel analytic framework that identifies “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. Finally, using several lines of empirical evidence, we identify relevant cell types, predict target genes, and propose putative causal mechanisms for fine-mapped variants. In total, our study provides an analytic framework for single-variant and single-cell analyses to elucidate putative causal variants and cell types from GWAS and high-resolution epigenomic assays.