In a recent study posted to the medRxiv* preprint server, researchers described the second update on the study of human genetic architecture concerning the effect of coronavirus disease 2019 (COVID-19).

Study: A second update on mapping the human genetic architecture of COVID-19. Image Credit: MIA Studio/Shutterstock

Globally, a complete of 651.9 million confirmed cases of COVID-19, including 6.6 million deaths, have been reported. Studies have investigated the assorted facets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its impact on the human body to combat the morbidity attributable to COVID-19. Understanding the function of host genetic aspects involved in COVID-19 susceptibility and severity is important to disclose the underlying mechanisms that may affect adversarial disease outcomes and facilitate novel drug development.

In regards to the study

In the current study, researchers presented the second update of the genome-wide association study (GWAS) related to SARS-CoV-2 infection susceptibility and severity derived from the COVID-19 Host Genetic Initiative (HGI).

The team performed the meta-analysis of three phenotypes noted in over 82 studies obtained from 35 countries, which included 36 studies having non-European ancestry. The three phenotypes included critical illness, hospitalization, and SARS-CoV-2 infection. Most of those studies were obtained before the widespread availability of the SARS-CoV-2 vaccines. The team compared the effect size and the statistical significance between prior and current analyses.

Two-class Bayesian models were employed for categorizing loci as having a better likelihood of being involved in either infection severity or susceptibility. Moreover, the team mapped the candidate causal genes onto biological pathways and performed a phenome-wide association assessment.     

Results

The study results found 21, 40, and 30 loci corresponding to SARS-CoV-2 infection, hospitalization, and important illness, respectively. Almost 51 significant loci across the genome were noted for the three phenotypes, adding 28 noteworthy loci to the previously identified 23 loci from the COVID-19 HGI. After the variety of phenotypes assessed was adjusted, 46 loci remained significant.

The Bayesian model showed that 366 loci were significantly more more likely to influence disease severity and hospitalization; nine loci could affect susceptibility to COVID-19, while six loci couldn’t be categorized. The team noted that the 1q22 locus had remarkable heterogeneity in effect size across ancestries, while the previously noted heterogenous locus FOXP4 displayed an analogous significance level to that detected previously.

Phenome-wide association evaluation showed that 15 of the whole 51 loci identified may very well be related to three essential pathways which can be involved in COVID-19 severity and susceptibility, namely (1) viral entry, (2) defense against viral entry in airway mucus, and (3) type 1 interferon (IFN) response. Moreover, the evaluation detected nine loci related to maintaining healthy lung tissue. Of those, five loci included candidate causal genes related to the viral entry pathway, including angiotensin-converting enzyme-2 (ACE-2), ABO, and transmembrane serine proteinase 2 (TMPRSS2). This supported the association between COVID-19 susceptibility and ABO blood groups due to the interaction of anti-B and anti-A antibodies with the SARS-CoV-2 spike protein, which interferes with viral entry. 4 of the nine detected loci included candidate causal genes related to viral entry defense throughout the airway mucus.    

The team also found that the 1q22 locus comprised an intergenic lead variant that reduced the danger of SARS-CoV-2 infection and increased MUC1 expression throughout the esophagus mucosa. Furthermore, the 1q22 locus comprised an independent lead variant that reduced the danger for COVID-19-related hospitalization but not SARS-CoV-2 infection, suggesting different potential mechanisms throughout the locus. Moreover, six loci included candidate causal genes related to the sort 1 interferon pathway. A lead variant of IFN-α-10 (IFNA10) within the IFN-α gene cluster increased the danger for SARS-CoV-2-associated critical illness. Moreover, on the genes that facilitated signaling downstream of IFN-α receptor (IFNAR), the team identified a lead variant that protected against hospitalization and important illness.    

Conclusion

The study findings showed that the second update of the GWAS enhanced the present understanding of host genetics involved in COVID-19 severity and susceptibility by detecting additional 28 loci. This improved variety of loci facilitates the mapping of genes to corresponding pathways involved in SARS-CoV-2 entry, defense in airway mucus, and the response of the immune system. The researchers imagine that further study is required to evaluate how COVID-19 severity and susceptibility loci mapped to distinct pathways provide information related to the impact of COVID-19 on human genetic architecture.

*Vital notice

medRxiv publishes preliminary scientific reports that should not peer-reviewed and, due to this fact, mustn’t be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.