Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases. The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.