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.

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