Association ofCXCR6with COVID-19 severity: Delineating the host genetic factors in transcriptomic regulation
Abstract
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 ofCXCR6andCCR9genes. These two genes have a protective effect on the lung and a risk effect on whole blood, respectively. The colocalization analysis of GWAS andcis-expression quantitative trait loci highlighted the regulatory effect onCXCR6expression in lung and immune cells. In the lung resident memory CD8+T (TRM) cells, we found a 3.32-fold decrease of cell proportion and lower expression ofCXCR6in the severe than moderate patients using the BALF transcriptomic dataset. Pro-inflammatory transcriptional programs were highlighted in TRMcells trajectory from moderate to severe patients.
Conclusions
CXCR6from the3p21.31locus is associated with severe COVID-19.CXCR6tends to have a lower expression in lung TRMcells of severe patients, which aligns with the protective effect ofCXCR6from TWAS analysis. We illustrate one potential mechanism of host genetic factor impacting the severity of COVID-19 through regulating the expression ofCXCR6and TRMcell proportion and stability. Our results shed light on potential therapeutic targets for severe COVID-19.
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