Association of CXCR6 with COVID-19 severity: Delineating the host genetic factors in transcriptomic regulation

BACKGROUND: The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~80% asymptomatic or mild cases and ~5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. METHODS: We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. RESULTS: We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on the lung and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung resident memory CD8(+) T (T(RM)) cells, we found a 3.32-fold decrease of cell proportion and lower expression of CXCR6 in the severe than moderate patients using the BALF transcriptomic dataset. Pro-inflammatory transcriptional programs were highlighted in T(RM) cells trajectory from moderate to severe patients. CONCLUSIONS: CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung T(RM) cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis. We illustrate one potential mechanism of host genetic factor impacting the severity of COVID-19 through regulating the expression of CXCR6 and T(RM) cell proportion and stability. Our results shed light on potential therapeutic targets for severe COVID-19.