Department of Human Genetics, McGill University, Montréal, QC, Canada.
Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
Nat Commun. 2023 Oct 4;14(1):6198. doi: 10.1038/s41467-023-41912-4.
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 cis-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 OAS1, ATP11A, DPP9 and NPNT, is associated with COVID-19 severity. MUC1 and PMF1 splicing is associated with COVID-19 susceptibility. Colocalization analyses support a shared genetic mechanism between COVID-19 severity with idiopathic pulmonary fibrosis at the ATP11A and DPP9 loci, and with chronic obstructive lung diseases at the NPNT locus. Last, we show that ATP11A, DPP9, NPNT, and MUC1 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.
可变剪接在异构体中产生功能多样性，影响对感染的免疫反应。在这里，我们通过对顺式剪接数量性状位点和 COVID-19 宿主遗传学倡议的结果进行两样本 Mendelian 随机化，评估可变剪接在 COVID-19 严重程度和易感性中的因果作用。我们发现，与 COVID-19 严重程度相关的是肺中的可变剪接，而不是 OAS1、ATP11A、DPP9 和 NPNT 的总表达。MUC1 和 PMF1 的剪接与 COVID-19 的易感性相关。共定位分析支持 COVID-19 严重程度与 ATP11A 和 DPP9 基因座特发性肺纤维化以及 NPNT 基因座慢性阻塞性肺疾病之间存在共同的遗传机制。最后，我们表明，ATP11A、DPP9、NPNT 和 MUC1 在 COVID-19 未感染和感染样本的肺肺泡上皮细胞中均高度表达。这些发现阐明了肺中可变剪接在 COVID-19 和呼吸道疾病中的重要性，为药物发现提供了基于异构体的靶标。
