African human variants that potentially impact the outcome of SARS-CoV-2 infection

Abstract

Introduction: The SARS-CoV-2 pandemic has had an unprecedented global impact, resulting in millions of confirmed cases and deaths. However, the severity and death rates varied among different ethnicities and geographical regions, suggesting associations between host genetics and infection outcomes as reported in SARS-CoV-2 Genome-Wide Association Studies (GWAS). These studies predominantly focused on non-African populations, leaving a significant knowledge gap regarding genetic variants influencing SARS-CoV-2 infection outcomes in African populations whose allele frequencies may significantly differ from those of non-African populations. This study aimed to address this gap by identifying human variants impacting SARS-CoV-2 infection outcomes primarily using GWAS-identified variants from non-African populations and analyzing their frequencies and potential impact in African populations. Methods: Using the Genome Aggregation Database (gnomAD) as a reference, allele frequency estimates were retrieved for GWAS-identified SNPs from SARS-CoV-2 GWAS databases. Common and rare variants that potentially impact SARS-CoV-2 susceptibility and infection outcomes within African population were identified using the allele frequency information and a pairwise fixation index test (FST test) was conducted to assess the extent of genetic differentiation of these variants between African and non-African populations. Missense variants associated with COVID-19 outcomes were further identified, and linkage disequilibrium (LD) analyses of these variants were performed. Additionally, Gene Ontology (GO) pathway enrichment analysis was conducted to explain pathways relevant to infection outcomes. Results: Only a subset (40%) of SNPs identified were common and rare within the African population. FST tests indicated significant genetic differentiation between African and non-African populations. 29 missense variants associated with COVID-19 outcomes were present in 17 genes and associated with infection, critical illness, and hospitalization. High LD (R2 > 0.8) was observed with the common missense variants. GO pathway enrichment analysis unveiled 34 biological pathways linked to COVID-19 outcomes, with 2'-5'-Oligoadenylate Synthetase (OAS) activity and Cytokine-Mediated Signaling Pathway being particularly significant. Conclusion: These findings offer valuable insights into the possible genetic determinants of COVID-19 outcomes in African populations. The study underscores the need for further research to explain the precise mechanisms underlying these associations and paves the way for personalized therapies targeted at individual genetic profiles. This knowledge could be pivotal in combating not only existing but also future coronavirus infections, thereby contributing to public health preparedness.