ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy

Rosanna Asselta; Elvezia Maria Paraboschi; Alberto Mantovani; Stefano Duga

Focusing specifically on common exonic variants, 4 SNPs showed significantly (P<2.2*10-16) different frequencies when comparing the Italian population with East Asians (and with Europeans) ( Table 2B ); 3 of them are synonymous variants, whereas one is the missense substitution p.Val160Met, which impacts on a residue far from the serine protease catalytic triad. This variant was previously found significantly associated with genomic rearrangements involving TMPRSS2, with the risk of prostate cancer 26 and with shorter time to prostate cancer diagnosis for high-risk patients. 27 Concerning eQTLs, a number of variants significantly impacting on TMPRSS2 expression in the lung (GTex data) are reported in the 3' region of the gene ( Figure 1B ). In Table 2C , a list of the most significant (P<1*10-8), together with their GnomAD frequencies in the East Asian and European populations, are reported. As for the Italian frequencies, we took advantage of the genome-wide association study (GWAS) performed on the above-described cohort (for a total of 3,284 individuals); 14 in this case, we had to infer genotype frequencies by an imputation approach (for details, see Supplementary Methods). Interestingly, all these eQTLs appear to have extremely . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.