SARS-CoV-2 susceptibility and ACE2 gene variations within diverse ethnic backgrounds

BackgroundHost genetics play a major role in COVID-19 susceptibility and severity. Here, we analyse an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (UK) to assess the association between variants in the ACE2 locus and COVID-19 risk. MethodsWe analysed whole-genome sequencing (WGS) data of 6,274 participants who were tested for SARS-CoV-2 from the UKs 100,000 Genomes Project (100KGP) for the presence of ACE2 coding variants and expression quantitative trait loci (eQTLs). FindingsWe identified a splice site variant (rs2285666) associated with increased ACE2 expression with an overrepresentation in SARS-CoV-2 positive patients relative to 100KGP controls (p = .015), and in hospitalised European patients relative to outpatients in intra-ethnic comparisons (p = .029). We also compared the prevalence of 288 eQTLs, of which 23 were enriched in SARS-CoV-2 positive patients. The eQTL rs12006793 had the largest effect size (d = 0.91), which decreases ACE2 expression and is more prevalent in controls, thus potentially reducing risk of COVID-19. We identified three novel nonsynonymous variants predicted to alter ACE2 function, and showed that three variants (p.K26R, p.H378R, p.Y515N) alter receptor affinity for the viral Spike (S) protein. Variants p.K26R and p.N720D are more prevalent in the European population (p < .001), but Y497H is less prevalent compared to East Asians (p = .020). InterpretationOur results demonstrate that the spectrum of genetic variants in ACE2 may inform risk stratification of COVID-19 patients and could partially explain the differences in disease susceptibility and severity among different ethnic groups. FundingThe 100KGP is funded by the National Institute for Health Research and NHS England. Funding was also obtained from Stanford University, Palo Alto.