Altered Blood Cell Traits Underlie a Major Genetic Locus of Severe COVID-19

Background: 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 associated with the 3p21.31 locus, we first performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310 999 European individuals from the UK Biobank. For genes potentially regulated by the COVID-19 risk variant, we examined associations between their expression and the polygenic score (PGS) of 1263 complex traits in a meta-analysis of 31 684 blood samples. For the prioritized blood cell traits, we tested their associations with age and sex in the same UK Biobank sample. Results: Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07 x 10(-8), 4.09 x 10(-13)), eosinophil count and percentage (p = 5.73 x 10(-3), 2.20 x 10(-3)), and neutrophil percentage (p = 3.23 x 10(-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 = 5.73 x 10(-21), 5.08 x 10(-19)); CCR2 with monocytes (p = 2.40 x 10(-10)); and CCR1 with monocytes and neutrophil (p = 1.78 x 10(-6), 7.17 x 10(-5)). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups. Conclusions: Our findings suggest that altered blood cell traits, especially those of monocyte, eosinophil, and neutrophil, may represent the mechanistic links between the genetic locus 3p21.31 and severe COVID-19. They may also underlie the increased risk of severe COVID-19 in older adults and men.