Alternative splicing in lung influences COVID-19 severity and respiratory diseases
説明
<jats:title>Abstract</jats:title><jats:p>Alternative splicing generates functional diversity in isoforms, impacting immune response to infection. Here, we evaluate the causal role of alternative splicing in COVID-19 severity and susceptibility by applying two-sample Mendelian randomization to <jats:italic>cis</jats:italic>-splicing quantitative trait loci and the results from COVID-19 Host Genetics Initiative. We identify that alternative splicing in lung, rather than total expression of <jats:italic>OAS1</jats:italic>, <jats:italic>ATP11A</jats:italic>, <jats:italic>DPP9</jats:italic> and <jats:italic>NPNT</jats:italic>, is associated with COVID-19 severity. <jats:italic>MUC1</jats:italic> and <jats:italic>PMF1</jats:italic> splicing is associated with COVID-19 susceptibility. Colocalization analyses support a shared genetic mechanism between COVID-19 severity with idiopathic pulmonary fibrosis at the <jats:italic>ATP11A</jats:italic> and <jats:italic>DPP9</jats:italic> loci, and with chronic obstructive lung diseases at the <jats:italic>NPNT</jats:italic> locus. Last, we show that <jats:italic>ATP11A, DPP9, NPNT</jats:italic>, and <jats:italic>MUC1</jats:italic> are highly expressed in lung alveolar epithelial cells, both in COVID-19 uninfected and infected samples. These findings clarify the importance of alternative splicing in lung for COVID-19 and respiratory diseases, providing isoform-based targets for drug discovery.</jats:p>
収録刊行物
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- Nature Communications
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Nature Communications 14 (1), 2023-10-04
Springer Science and Business Media LLC
