key: cord-0327701-qauso93y
authors: Patil, S.; Pemmasani, S. K.; Chitturi, N.; Bhatnagar, I.; Acharya, A.; Subash, L. V.
title: COVID-19 and Indian population: a comparative genetic analysis
date: 2021-12-15
journal: nan
DOI: 10.1101/2021.12.15.21267816
sha: 83b8320332d6c66f4f0f68958b00394d272f030f
doc_id: 327701
cord_uid: qauso93y

Background Major risk factors of COVID-19 include older age, male gender, and comorbidities. In addition, host genetic makeup is also known to play a major role in COVID-19 susceptibility and severity. To assess the genetic predisposition of the Indian population to COVID-19, a comparative analysis of the frequencies of polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and fatal outcomes was done between the Indian population and other major populations (European, African, East Asian, South Asian, and American). Materials and methods Polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and mortality were mined from genetic association studies, comparative genetic studies, expression quantitative trait loci studies among others. Genotype data of these polymorphisms were either sourced from the GenomegaDB database of Mapmygenome India Ltd. (sample size = 3054; Indian origin) or were imputed. Polymorphisms with minor allele frequency >= 0.05 and that are in Hardy-Weinberg equilibrium in the Indian population were considered for allele frequency comparison between the Indian population and 1000 Genome population groups. Results Allele frequencies of 421 polymorphisms were found to be significantly different in the Indian population compared to European, African, East Asian, South Asian, and American populations. 128 polymorphisms were shortlisted based on linkage disequilibrium and were analyzed in detail. Apart from well-studied genes, like ACE2, TMPRSS2, ADAM17, and FURIN, variants from AHSG, IFITM3, PTPN2, CD209, CCL5, HEATR9, SELENBP9, AGO1, HLA-G, MX1, ICAM3, MUC5B, CRP, C1GALT1, and other genes were also found to be significantly different in Indian population. These variants might be implicated in COVID-19 susceptibility and progression. Conclusion Our comparative study unraveled multiple genetic variants whose allele frequencies were significantly different in the Indian population and might have a potential role in COVID-19 susceptibility, its severity, and fatal outcomes. This study can be very useful for selecting candidate genes/variants for future COVID-19 related genetic association studies.

Coronavirus disease -2019 (COVID- 19) , caused by severe acute respiratory syndrome coronavirus 2 66 (SARS-CoV2), has strained the healthcare system and economy of a majority of nations and has 67 crippled the human population [1, 2, 3]. COVID-19 is characterized by a range of clinical features 68 which are categorized as most common, less common, and rare (severe). The most common 69 symptoms are fever, dry cough, and fatigue, while less common symptoms are pneumonia without 70 noticeable hypoxemia, sputum production, sore throat, headache, chest pain, and diarrhea [4, 5] . 71 Acute respiratory distress syndrome, sepsis, acute cardiac injury, heart failure, acute kidney injury, 72 hypoxic encephalopathy are more common in severe cases [4, 5, 6] . Severe patients show elevated 73 levels of pro-inflammatory cytokines, indicating the presence of cytokine storm [4]. Self-reported 74 loss of smell and taste was also observed in some cases [7] . 75

Major risk factors for COVID-19 severity are older age, male gender, and comorbidities. A higher 76 case fatality rate (CFR) has been observed in older adults as compared to the younger population [8, 77 9, 10, 11, 12]. Relatively fewer female deaths are consistently observed as compared to males [10, 78 11, 12]. COVID-19 patients with comorbidities like hypertension, obesity, diabetes, and others are 79 more likely to develop severe complications than ones without any underlying diseases [13, 14, 15, 80 16, 17, 18]. ABO blood groups also seem to be contributing to COVID-19 related risk. While blood 81 group A is associated with an increased risk of severe COVID-19 outcomes, blood group O seems to 82 be protective [19, 20, 21] . 83

In addition to the above risk factors, host genetics can modulate susceptibility and severity of the 84 disease by regulating viral entry and host immune response [22, 23] . For example, rs12329760 85 (p.Val197Met) affects the stability of TMPRSS2 protein, which is implicated in SARS-CoV2 viral 86 entry into host cells. This polymorphism was found to be less frequent in severe COVID-19 cases as 87 compared to others, suggesting its protective role against severe outcomes of COVID-19 [24] . The C 88 allele of rs12252 in the IFITM3 gene that is known for inhibiting influenza virus entry into host cells 89 was found to be a genetic risk factor for COVID- 19 genetics in COVID-19 susceptibility and severity in the Indian population, we analyzed the 96 frequencies of the polymorphisms that are directly or indirectly implicated in COVID-19. We have 97 also made a comparison between Indian and other populations to understand allele frequency 98 distribution globally. 99 (Table 1) , eighteen polymorphisms implicated in the immune response to SARS-CoV2 infection 145 (Table 2) , fifty-eight polymorphisms directly or indirectly associated with COVID-19 severity (Table  146 3), nine polymorphisms associated with COVID-19 related mortality/fatal outcomes (Table 4), and  147 twelve polymorphisms associated with comorbidities of COVID-19 (Table 5) Supplementary Table 3 ). In the 'COVID-19 susceptibility' category, the number of variants with the 163 highest risk allele frequency was less than the variants with the lowest risk allele frequency in the 164 IND population. A similar trend was observed in EAS and AFR populations. However, an opposite 165 trend was observed in EUR and AMR populations (Fig. 1A) . In IND and AFR populations, COVID-166 19 severity-related variants with the highest risk allele frequencies were more than the lowest 167 frequency variants, while in EAS, EUR, and AMR populations this was found to be opposite (Fig.  168 1B). The number of variants associated with COVID-19 related mortality and having the highest risk 169

allele frequency was less than the variants with the lowest risk allele frequency in IND, EAS, and 170 AFR populations, while in SAS and AMR only the highest frequency variants were observed (Fig.  171 1C). 172 173 4 DISCUSSION 174

SARS-CoV-2 gains entry into human cells by binding its spike protein to ACE2 receptors. ACE2, a 176 part of the renin-angiotensin-aldosterone system (RAAS), is crucial in regulating blood pressure and 177 maintaining electrolyte balance in the body, physiology of the heart, kidneys, and lungs [44, 45] . 178 Genetic variations in ACE2 are known to be associated with its increased expression levels in 179 COVID-19 patients. These variants affect ACE2 transcription/translation and also alter binding 180 affinity to SARS-CoV2 spike protein, thereby affecting the susceptibility to SARS- . 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. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 15, 2021. ; https://doi.org/10.1101/2021.12.15.21267816 doi: medRxiv preprint 0.078 (Table 4) , which is significantly greater than only the European population (0.046). Its 379 frequency is highest in the African population (0.256). 380 381

Twelve polymorphisms associated with comorbidities of COVID-19 were also analyzed (Table 5) 

Associations Between Genetically Predicted Protein Levels and COVID-674

Vitamin D deficiency is associated with COVID-19 positivity 676 and severity of the disease

Does vitamin D deficiency increase the 678 severity of COVID-19?

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SPEG interacts with myotubularin, and its deficiency 683 causes centronuclear myopathy with dilated cardiomyopathy

Molecular insights into cardiomyopathies 686 associated with desmin (DES) mutations

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Impact of population density on Covid-19 infected and 692 mortality rate in India

Implications of the second wave of COVID-19 in 695

Effects of host genetic variations on response to, 697 susceptibility and severity of respiratory infections

Dectin-1 and DC-SIGN polymorphisms 700 associated with invasive pulmonary Aspergillosis infection

Evaluación de 704 variantes en los genes IL6R, TLR3 y DC-SIGN asociadas con dengue en una población colombiana 705 muestreada

Variability in genes related to 708 SARS-CoV-2 entry into host cells (ACE2, TMPRSS2, TMPRSS11A, ELANE, and CTSL) and its 709 potential use in association studies

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Dipeptidyl peptidase-4 (DPP4) inhibition in 714 COVID-19

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HNF1α induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from 720 evolutionarily conserved promoter motifs

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IFITM proteins promote SARS-CoV-2 infection 726 and are targets for virus inhibition in vitro

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CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in 735

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The African-American population with a low allele frequency of SNP rs1990760 752 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 753 infection

The interferon gamma gene polymorphism +874 A/T is 755 associated with severe acute respiratory syndrome

Studying the 758 impact of nutritional immunology underlying the modulation of immune responses by nutritional 759 compounds-a review

The 677C→T variant of MTHFR is the major genetic 762 modifier of biomarkers of folate status in a young, healthy Irish population

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Angiopoietin-2 as a marker of endothelial 767 activation is a good predictor factor for intensive care unit admission of COVID-19 patients

A dramatic rise in serum ACE2 activity in a 770 critically ill COVID-19 patient

SARS-CoV-2 Receptor ACE2 Gene Is Associated with 772

Hypertension and Severity of COVID 19: Interaction with Sex, Obesity, and Smoking

Polymorphisms in the 775 ACE2 locus associate with severity of COVID-19 infection

Genomic atlas of the human plasma proteome. 778 Nature

Elevated level of C-reactive protein may be an early marker to predict risk for severity 780 of COVID-19

CRP-level-associated polymorphism rs1205 within the 784 CRP gene is associated with 2-hour glucose level: The SAPPHIRe study

CRP/IL-6/IL-10 Single-Nucleotide Polymorphisms Correlate 787 with the Susceptibility and Severity of Community-Acquired Pneumonia

Association of ICAM3 genetic variant with severe acute 791 respiratory syndrome

IL1RN coding variant is associated with lower risk of acute 793 respiratory distress syndrome and increased plasma IL-1 receptor antagonist

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Post-COVID-19 pneumonia lung fibrosis: a worrisome sequelae in 802 surviving patients

A common MUC5B promoter polymorphism and 805 pulmonary fibrosis

Common variants at 21q22.3 locus influence MX1 807 and TMPRSS2 gene expression and susceptibility to severe COVID-19. iScience

Genetic variants are identified to increase risk of 810 COVID-19 related mortality from UK Biobank data