biostudies-literatureNakanishi TMEXT | Japan Society for the Promotion of SciencePublic Health Agency of CanadaCancer Research UKMedical Research CouncilFonds de Recherche du Québec - SantéNational Institute for Health Research (NIHR)Canada Foundation for InnovationWellcome TrustGouvernement du Canada | Canadian Institutes of Health Research6198https://www.ebi.ac.uk/biostudies/studies/S-EPMC10550956biostudies-literatureUnknown14(1)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, DPPNature communicationsAlternative splicing in lung influences COVID-19 severity and respiratory diseases.PMC10550956221680/Z/20/Z365825; 409511, 100558, 169303C18281/A2901922KJ1190, 22J30004, 23H02917476575Richards JBWillett JGuillen-Guio BAllen RJZhou SAdra DNakanishi TFarjoun YfalseAlternative splicing in lung influences COVID-19 severity and respiratory diseases.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, DPP2023-01-01T00:00:00Z2023 Oct2026-05-29T07:13:30.511Z2024-11-15T01:39:35.833ZS-EPMC105509563779407410.1038/s41467-023-41912-4