Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

Eric W. Stawiski; Devan Diwanji; Kushal Suryamohan; Ravi Gupta; Frederic A. Fellouse; J. Fah Sathirapongsasuti; Jiang Liu; Ying-Ping Jiang; Aakrosh Ratan; Monika Mis; Devi Santhosh; Sneha Somasekar; Sangeetha Mohan; Sameer Phalke; Boney Kuriakose; Aju Antony; Jagath R. Junutula; Stephan C. Schuster; Natalia Jura; Somasekar Seshagiri

Analysis of S-protein RBD domain of SARS-CoV-2, SARS-CoV and closely related bat CoV RaTG13 identified changes that have increased the affinity of CoV-2 S1 RBD for human ACE2, which likely contributes to its increased infectivity . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.07.024752 doi: bioRxiv preprint 5 Wrapp et al., 2020) . It is very likely that there are natural variations in ACE2 in human populations, though not under selection, that may increase or decrease its affinity to SARS-CoV-2 S-protein and thereby render individuals more resistant or susceptible to the virus. To investigate this, we assessed ACE2 protein-altering variations from a number of databases including the gnomAD (Karczewski et al., 2019) , RotterdamStudy (Ikram et al., 2017) , ALSPAC (Fraser et al., 2013) and Asian-specific databases which included GenomeAsia100k (GenomeAsia, 2019), HGDP (Bergstrom et al., 2020) , TOMMO-3.5kjpnv2 (Tadaka et al., 2019) , and IndiGen (https://indigen.igib.in/), and HGDP (Bergstrom et al., 2020) (Supplementary Table 1 ). We found a total of 298 unique protein altering variants across 256 codons distributed throughout the 805 amino acid long human ACE2 (Figure 1a Table 1 ). The most frequent variant, N720D (1.6% allele frequency; n=3054, gnomAD), was found in the C-terminal collectrin domain that is not involved in the SARS-CoV-2 Sprotein interaction. Overall, we found human ACE2 receptor polymorphisms to be low with a weighted mean Fst (fixation index) value of 0.0168, and the ACE2 PD showed Table 1) .