Rare host variants in ciliary expressed genes contribute to COVID-19 severity in Bulgarian patients

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pneumonia with extremely heterogeneous clinical presentation, ranging from asymptomatic to severely ill patients. Previous studies have reported links between the presence of host genetic variants and the outcome of the COVID-19 infection. In our study, we used whole exome sequencing in a cohort of 444 SARS-CoV-2 patients, admitted to hospital in the period October-2020-April-2022, to search for associations between rare pathogenic/potentially pathogenic variants and COVID-19 progression. We used gene prioritization-based analysis in genes that have been reported by host genetic studies. Although we did not identify correlation between the presence of rare pathogenic variants and COVID-19 outcome, in critically ill patients we detected known mutations in a number of genes associated with severe disease related to cardiovascular disease, primary ciliary dyskinesia, cystic fibrosis, DNA damage repair response, coagulation, primary immune disorder, hemoglobin subunit β, and others. Additionally, we report 93 novel pathogenic variants found in severely infected patients who required intubation or died. A network analysis showed main component, consisting of 13 highly interconnected genes related to epithelial cilium. In conclusion, we have detected rare pathogenic host variants that may have influenced the COVID-19 outcome in Bulgarian patients.

Keywords: COVID-19 severity and outcome; Cilia dysfunction; Host genetic variants; Rare protein-coding variants; SARS-CoV-2; WES.

Fig. 1

Exome data of the studied cohort. (A) Principal components analysis (PCA) with 1,000 Genomes Project. COVID-19 samples from our study (black) and 1000 Genomes samples are plotted together based on principal components from overlapping SNP data. Five super populations: EUR, European; ASN, Asian; AMR, Ad Mixed American; AFR, African. (B) Quantile–Quantile (QQ) plot of association results for all variants; (C) QQ plot of association results for rare variants.

Fig. 2

Whole exome sequencing data. (a) Distribution of variants by type and functional consequences. (b) By allele frequency (AF) according to population databases.

Fig. 3

STRING network analysis demonstrating interaction between 244 risk proteins carrying 519 pathogenic/likely pathogenic variants. Legend: Network nodes represent proteins and edges represent protein–protein associations with a confidence score ≥ 0.4 as the threshold. Clusters are defined as subgraphs with any two nodes (genes) connected to each other by edges (representing protein-protein association), and not connected to other nodes in the graph. Networks containing less than three interacting proteins are not shown on the figure. risk protein, and networks 52–60 did not have any protein interaction with other human proteins. Cluster 2 containing genes involved in the epithelium cell movement is marked.