The major genetic risk factor for severe COVID-19 among Europeans does not show any association among Indian populations


 With the growing evidence on the variable human susceptibility against COVID-19, it is clear that there are some genetic loci modulating the severity. Recent studies have identified several loci associated with the higher severity. More recently, a study has identified 50kb segment introgressed from Neanderthal adding risk for COVID-19, and is present among 16% and 50% people of European and South Asian origin respectively. Contrary to that, our studies on ACE2 identified a haplotype present among 20% and 60% of European and South Asian populations respectively, was probably responsible for the low case fatality ratio among South Asian populations. This result was also consistent with the realtime infection rate and case fatality ratio among various states of India. We readdressed this issue using both of the contrasting datasets and compared them with the realtime infection rates and case fatality ratio in India. We found out that that the polymorphism present in 50kb introgressed segment (rs10490770) did not show any significant correlation with the realtime infection and case fatality ratio in India.With the growing evidence on the variable human susceptibility against COVID-19, it is clear that there are some genetic loci modulating the severity. Recent studies have identified several loci associated with the higher severity. More recently, a study has identified 50kb segment introgressed from Neanderthal adding risk for COVID-19, and is present among 16% and 50% people of European and South Asian origin respectively. Contrary to that, our studies on ACE2 identified a haplotype present among 20% and 60% of European and South Asian populations respectively, was probably responsible for the low case fatality ratio among South Asian populations. This result was also consistent with the realtime infection rate and case fatality ratio among various states of India. We readdressed this issue using both of the contrasting datasets and compared them with the realtime infection rates and case fatality ratio in India. We found out that that the polymorphism present in 50kb introgressed segment (rs10490770) did not show any significant correlation with the realtime infection and case fatality ratio in India.


Introduction
Since the beginning of COVID-19 pandemic, it has been observed that people with different ethnic background/country/continent have variable degrees of susceptibility.
Though there are a few well known factors for higher susceptibility, e.g. age and comorbidity (Alberca et al. 2020;Fang et al. 2020), the disease variability has been also reported among the healthy people (Godri Pollitt et al. 2020). Recent genome wide association study has identified several loci on chromosome 3 associated with the severe risk factor for COVID-19 among Europeans (COVID-19 Host Genetics Initiative 2020; Ellinghaus et al. 2020). Subsequently, Zeberg (Zeberg and Pääbo 2020) have identified a risk haplotype of 50kb introgressed from Neanderthal, which they called as 'Neanderthal core haplotype'. This risk haplotype was present with an allele frequency of 30% among south Asians, 8% in Europeans and 4% among African-Americans. The peak carrier frequency was estimated among Bangladeshi population, where 63% carried at least one copy of this haplotype. The study has also cited twice risk of mortality of Bangladeshi in the UK than native population (Public Health England 2020).
Conversely, three of our studies on ACE2, the gateway of SARS-CoV-2, identified a haplotype, shared among South Asians and East Eurasians, likely protecting them from severe risk (Srivastava et al. 2020a, b;Singh et al. 2020). Additionally, the spatial distribution of this haplotype showed strong association with the low infection as well as case fatality rate (CFR) (Srivastava et al. 2020a). To resolve this discrepancy, we have extracted a SNP (rs10490770) reported to be associated with the high risk for COVID-19 (Zeberg and Pääbo 2020)

Materials and method
The genomewide genotype data by Illumina has tagged rs2285666 and rs10490770 SNPs in their panel, therefore we searched the genotype datasets generated by this platform.
The frequency data for both of the SNPs, from various Indian populations were extracted by using Plink 1.9 (Chang et al. 2015), from 1000 genome project data phase 3 (1000

Results and Discussion
In contrast with the conclusions drawn by Zeberg (Zeberg and Pääbo 2020), our work on ACE2 have identified a haplotype frequent among South Asians and East Eurasians (Srivastava et al. 2020a, b;Singh et al. 2020). This haplotype is derived by a polymorphism rs2285666 responsible for elevated expression of ACE2. We have found high inverse correlation of this haplotype with the statewise cases as well as case fatality ratio among Indian populations (Srivastava et al. 2020a). This correlation was significant at various timelines of the pandemic in India (Table 1). We verified the statistical tests with the updated data upto December 2020 and found it consistent with the previous observations ( Fig. 1). Thus, it is likely that the ACE2 SNP rs2285666 has played a significant role in modulating the susceptibility among Indian populations.
In our search of SNPs reported at high risk by Zeberg (Zeberg and Pääbo 2020), we found rs10490770 from genomewide datasets (Chaubey et al. 2011(Chaubey et al. , 2017Metspalu et al. 2011;Tamang et al. 2018;Pathak et al. 2018). We applied the same tests done for the ACE2 SNPs ( Fig. 1). The statewise frequency variation of this SNP did not show any association either with the number of cases or case fatality ratio (Table 1). We repeated these regression tests for the number of cases as well as case fatality ratio data, obtained during all the three months. However, none of them showed any association with the rs10490770 (p > 0.3) ( Table 1). The lack of association is striking and suggesting complex susceptibility response among Indian populations.
Zeberg (Zeberg and Pääbo 2020) has used the data of higher susceptibility to Bangladeshi population living in UK (Aldridge et al. 2020) to support their findings. The higher mortality rate for Bangladeshi population in the UK needs more detailed investigation on comorbidity, relative age, genetic admixture as well as local environment. More importantly, a similar trend has also been observed among African-Americans (Hooper et al. 2020;Kullar et al. 2020;Yancy 2020). Furthermore, it is notable that among the Bangladeshi samples analysed by us, the tribal populations of Bangladesh showed almost three times less frequency of rs10490770 (Supplementary Table 1). Therefore, it is advised to explicitly mention the caste and tribal populations while making any statement about South Asian populations.
Thus, our extensive analyses on realtime data did not show any association of the SNP rs10490770 with the state-wise infection rates as well as CFRs, suggesting that the risk allele for COVID-19 in Europe doesn't play a significant role in COVID-19 severity in India.

Data Availability Statement
All datasets generated for this study are included in the article/Supplementary Material.

Conflict of Interest
Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.