Additional Supporting Materials for Zhou et al 2021 Gerontology

<b>Background:</b> The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown. <b>Methods:</b> 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. <b>Results:</b> Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (<i>p</i> = 1.07x10^-8<i>,</i> 4.09x10^-13), eosinophil count and percentage (<i>p</i> = 5.73x10^-3, 2.20x10^-3), and neutrophil percentage (<i>p</i> = 3.23x10^-3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: <i>CCR3</i> with eosinophil and basophil (<i>p</i> = 5.73x10^-21, 5.08x10^-19); <i>CCR2</i> with monocytes (<i>p</i> = 2.40x10^-10); and <i>CCR1</i> with monocytes and neutrophil (<i>p</i> = 1.78x10^-6, 7.17x10^-5). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups. <b>Conclusions:</b> 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.