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Altered blood cell traits underlie a major genetic locus of severe COVID-19

Purpose: The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown. Methods: To identify intermediate traits of the COVID-19 risk variant, we performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310,999 European individuals from UK Biobank. For candidate target genes, we examined associations between their expression and the polygenic score (PGS) of 1,263 complex traits in a meta-analysis of 31,684 blood samples. Results: Our PheWAS identified and replicated multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07e-8, 4.09e-13), eosinophil count and percentage (p = 5.73e-3, 2.20e-3), and neutrophil percentage (p = 3.23e-3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73e-21, 5.08e-19); CCR2 with monocytes (p = 2.40e-10); and CCR1 with monocytes and neutrophil (p = 1.78e-6, 7.17e-5). Conclusions: Multiple blood cell traits, especially monocyte, eosinophil, and neutrophil numbers, are associated with the COVID-19 risk variant and the expression of its candidate target genes, representing probable mechanistic links between the genetic locus 3p21.31 and severe COVID-19.