Understand variability of COVID-19 through population and tissue variations in expression of SARS-CoV-2 host genes.

An urgent question of coronavirus disease 2019 (COVID-19) is population variation in susceptibility to SARS-CoV-2 infection and symptom severity. We explore the expression profiles of SARS-CoV-2 host genes, their population variations, associated genetic variants, age- and sex-dependency in normal individuals. SARS-CoV-2 host genes are provisionally defined as the human genes that are experimentally validated or bioinformatically predicted to interact with SARS-CoV-2 proteins. Genes exhibiting most variable expression include ACE2, CLEC4G, CLEC4M, CD209 (interact with the SARS-CoV-2 spike protein); REEP6 (a receptor accessory protein expressed in the olfactory epithelium); SLC27A2 and PKP2 (inhibit virus replication); and PTGS2 (mediates fever response). SNP rs4804803, associated with SARS severity, affects expression of CLEC4G and CD209. Genetic variants of proteases associated with SARS-CoV-2 entry (TMPRSS2, CTSB, and CTSL) are strongly associated with their expression variation, suggesting a genetic contribution to phenotypic variations in multiple organs upon virus attack. The most significant age-dependent gene is ACE2, the cellular receptor of SARS-CoV-2. Others include TGF-β family member GDF15, mediating inflammation, and VKORC1, possibly explaining vitamin K deficiency in COVID-19. TIMM10 and ERGIC1 exhibit significant sex differences. In summary, our results show genetic and multiple biological variables may underlie the population variation in SARS-CoV-2 infection and symptom severity.