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 1,263 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 = 1.07×10 -8, 4.09×10 -13), eosinophil count and percentage (p = 5.73×10 -3, 2.20×10 -3), and neutrophil percentage (p = 3.23×10 -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 = 5.73×10 -21, 5.08×10 -19); CCR2 with monocytes (p = 2.40×10 -10); and CCR1 with monocytes and neutrophil (p = 1.78×10 -6, 7.17×10 -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.
Altered blood cell traits underlie a major genetic locus of severe COVID-19