Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules

Neutrophils are essential immune cells loaded with cytosolic granules that contain potent antimicrobial and immunostimulatory molecules. Alterations of neutrophil granule contents are associated with immunodeficiency and hyperinflammation. Identification of regulators of granule development can aid in understanding of neutrophil-driven pathologies. Here, we perform a systematic prioritization of genetic variants associated with neutrophil cytometric side scatter (SSC), a proxy for granularity, identified in a genome-wide association study (GWAS) of blood parameters in healthy individuals. We show that triangulation of GWAS data with epigenetic and eQTL data identifies previously unknown factors regulating neutrophil granularity. We validate this approach using cellular and animal models to confirm that cyclin dependent kinase 6 (encoded by CDK6) regulates neutrophil granule development. CDK6 specifically regulates the abundance of primary granules without affecting neutrophil maturation. Our approach demonstrates the utility of cell counter-derived SSC data paired with genomics as a tool to investigate neutrophil development and function.