Case–control association study between polygenic risk score and COVID-19 severity in a Russian population using low-pass genome sequencing

The course of COVID-19 is highly variable, with genetics playing a significant role. Through large-scale genetic association studies, a link between single nucleotide polymorphisms and disease susceptibility and severity was established. However, individual single nucleotide polymorphisms identified thus far have shown modest effects, indicating a polygenic nature of this trait, and individually have limited predictive performance. To address this limitation, we investigated the performance of a polygenic risk score model in the context of COVID-19 severity in a Russian population. A genome-wide polygenic risk score model including information from over a million common single nucleotide polymorphisms was developed using summary statistics from the COVID-19 Host Genetics Initiative consortium. Low-coverage sequencing (5x) was performed for ~1000 participants, and polygenic risk score values were calculated for each individual. A multivariate logistic regression model was used to analyse the association between polygenic risk score and COVID-19 outcomes. We found that individuals in the top 10% of the polygenic risk score distribution had a markedly elevated risk of severe COVID-19, with adjusted odds ratio of 2.9 (95% confidence interval: 1.8-4.6, <i>p</i>-value = 4e-06), and more than four times higher risk of mortality from COVID-19 (adjusted odds ratio = 4.3, <i>p</i>-value = 2e-05). This study highlights the potential of polygenic risk score as a valuable tool for identifying individuals at increased risk of severe COVID-19 based on their genetic profile.