GWAS and polygenic risk score of severe COVID-19 in Eastern Europe

Abstract

Background: COVID-19 disease has infected more than 772 million people, leading to 7 million deaths. Although the severe course of COVID-19 can be prevented using appropriate treatments, effective interventions require a thorough research of the genetic factors involved in its pathogenesis.

Methods: We conducted a genome-wide association study (GWAS) on 7,124 individuals (comprising 6,400 controls who had mild to moderate COVID-19 and 724 cases with severe COVID-19). The inclusion criteria were acute respiratory distress syndrome (ARDS), acute respiratory failure (ARF) requiring respiratory support, or CT scans indicative of severe COVID-19 infection without any competing diseases. We also developed a polygenic risk score (PRS) model to identify individuals at high risk.

Results: We identified two genome-wide significant loci (P-value <5 × 10^-8) and one locus with approximately genome-wide significance (P-value = 5.92 × 10^-8-6.15 × 10^-8). The most genome-wide significant variants were located in the leucine zipper transcription factor like 1 (LZTFL1) gene, which has been highlighted in several previous GWAS studies. Our PRS model results indicated that individuals in the top 10% group of the PRS had twice the risk of severe course of the disease compared to those at median risk [odds ratio = 2.18 (1.66, 2.86), P-value = 8.9 × 10^-9].

Conclusion: We conducted one of the largest studies to date on the genetics of severe COVID-19 in an Eastern European cohort. Our results are consistent with previous research and will guide further epidemiologic studies on host genetics, as well as for the development of targeted treatments.

Keywords: COVID-19; GWAS; LZTFL1 gene; polygenic risk score; severe COVID-19.

Figure 1

Manhattan plot with the GWAS results for the severe COVID-19 phenotype (P-value < 5 × 10⁻⁸).

Figure 2

Scatter plot of comparison of odds ratios (OR) from the top associated SNPs from the COVID-19 Host Genetics Initiative with our results (OR_hgi indicates results from COVID-19 HGI GWAS and OR_gwas indicates results from the current study). Horizontal and vertical bars represent 95% confidence intervals.

Figure 3

Quantile plot of the severe course of COVID-19 PRS developed by LDPred2. The odds ratio represents comparison of PRS odds from different quantiles with the reference quantile (40%−60%). The bars represent the standard deviation (SD).