Genetic susceptibility to severe COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of the disease range from an asymptomatic condition to life-threatening events and death, with more severe courses being associated with age, male sex, and comorbidities. Besides these risk factors, intrinsic characteristics of the virus as well as genetic factors of the host are expected to account for COVID-19 clinical heterogeneity. Genetic studies have long been recognized as fundamental to identify biological mechanisms underlying congenital diseases, to pinpoint genes/proteins responsible for the susceptibility to different inherited conditions, to highlight targets of therapeutic relevance, to suggest drug repurposing, and even to clarify causal relationships that make modifiable some environmental risk factors. Though these studies usually take long time to be concluded and, above all, to translate their discoveries to patients' bedside, the scientific community moved really fast to deliver genetic signals underlying different COVID-19 phenotypes. In this Review, besides a concise description of COVID-19 symptomatology and of SARS-CoV-2 mechanism of infection, we aimed to recapitulate the current literature in terms of host genetic factors that specifically associate with an increased severity of the disease.

Keywords: COVID-19; Genetics; Genome-wide association study; Mutation; SARS-CoV-2; Severity.

Fig. 1

COVID-19 clinical manifestations. A. Cases infected by SARS-CoV-2 can be asymptomatic, or develop mild to critical disease. Most common symptoms are listed together with the identified risk factors. B. Observed fatality ratios per country. On the left: fatality ratios were defined as the number of deaths divided by the number of confirmed cases; the panel shows the 20 countries most affected by COVID-19 worldwide. On the right: the diagonal lines on the chart correspond to different case fatality ratios. Countries falling on the uppermost lines have the highest observed case fatality ratios. Points with a black border correspond to the 20 most affected shown in the left panel. Data derive from the https://coronavirus.jhu.edu/data/mortality site (maintained at the Johns Hopkins University, Coronavirus Resource center), accessed on December 28th, 2022.

Fig. 2

Different approaches to the study of COVID-19 genetics. A. Genetic studies on COVID-19 have focused mainly on two phenotypes: disease severity and susceptibility to infection. Alternative phenotypes (listed) and interaction analyses have tried to deepen the knowledge on host genetics. B. Summary of strategies used to unravel the genetic basis of COVID-19 severity.

Fig. 3

GWAS on common variants: summary of the top results. A. Karyotype plot of lead variants. The panel shows the distribution at the chromosome level of all genome-wide significant signals found in GWAS studies (listed in Table 1, Table 2). Loci are indicated with a red arrowhead, with the exception of the 3p21.31 locus, which is pointed out by a blue arrowhead. As for this locus, the table shows the 4 SNPs found in different GWAS. B. Regional plot for associations in the 3p21.31 region. The P values of the SNPs in this region refer to HGI analysis A2, release 7. The rs10490770 top SNP is shown as a purple diamond; all LD values were referred to this lead SNP. The 50-kb region evidenced with a vertical band in light grey correspond to the haplotype block introgressed from Neanderthals. C. and D. Mapping genome-wide significant signals. Panel C displays the distribution of the lead association signals with respect to refseq genes, whereas panel D shows the potential pathogenic impact of those signals mapping within coding genes. Panels A, C, and D were produced using the web-based variant annotation tool SNPnexus (https://www.snp-nexus.org/v4/) (Oscanoa et al., 2020). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Enrichment and String analyses for genome-wide significant signals. A. Pathways enrichment analysis. The analysis was performed using the Reactome database; enriched pathways are evidenced with different shades of yellow. The panel was produced using the web-based variant annotation tool SNPnexus (https://www.snp-nexus.org/v4/) (Oscanoa et al., 2020). B. String analysis. Interactions among proteins tagged by lead variants are indicated. The figure was prepared using String, the database of known and predicted protein-protein interactions (https://string-db.org/; (Szklarczyk et al., 2021)). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)