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Alternative splicing in lung influences COVID-19 severity and respiratory diseases

Author

Listed:
  • Tomoko Nakanishi

    (McGill University
    McGill University
    Kyoto University
    the University of Tokyo)

  • Julian Willett

    (McGill University
    McGill University
    McGill University)

  • Yossi Farjoun

    (McGill University
    Five Prime Sciences Inc)

  • Richard J. Allen

    (University of Leicester
    Leicester Respiratory Biomedical Research Centre, Glenfield Hospital)

  • Beatriz Guillen-Guio

    (University of Leicester
    Leicester Respiratory Biomedical Research Centre, Glenfield Hospital)

  • Darin Adra

    (McGill University)

  • Sirui Zhou

    (McGill University
    McGill University
    McGill University)

  • J. Brent Richards

    (McGill University
    Five Prime Sciences Inc
    McGill University
    King’s College London)

Abstract

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.

Suggested Citation

  • Tomoko Nakanishi & Julian Willett & Yossi Farjoun & Richard J. Allen & Beatriz Guillen-Guio & Darin Adra & Sirui Zhou & J. Brent Richards, 2023. "Alternative splicing in lung influences COVID-19 severity and respiratory diseases," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41912-4
    DOI: 10.1038/s41467-023-41912-4
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    1. L. Robert Hollingsworth & Humayun Sharif & Andrew R. Griswold & Pietro Fontana & Julian Mintseris & Kevin B. Dagbay & Joao A. Paulo & Steven P. Gygi & Daniel A. Bachovchin & Hao Wu, 2021. "DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation," Nature, Nature, vol. 592(7856), pages 778-783, April.
    2. Thorunn A. Olafsdottir & Fannar Theodors & Kristbjorg Bjarnadottir & Unnur Steina Bjornsdottir & Arna B. Agustsdottir & Olafur A. Stefansson & Erna V. Ivarsdottir & Jon K. Sigurdsson & Stefania Benoni, 2020. "Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Mark E. Davis & Jonathan E. Zuckerman & Chung Hang J. Choi & David Seligson & Anthony Tolcher & Christopher A. Alabi & Yun Yen & Jeremy D. Heidel & Antoni Ribas, 2010. "Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles," Nature, Nature, vol. 464(7291), pages 1067-1070, April.
    4. Athanasios Kousathanas & Erola Pairo-Castineira & Konrad Rawlik & Alex Stuckey & Christopher A. Odhams & Susan Walker & Clark D. Russell & Tomas Malinauskas & Yang Wu & Jonathan Millar & Xia Shen & Ka, 2022. "Whole-genome sequencing reveals host factors underlying critical COVID-19," Nature, Nature, vol. 607(7917), pages 97-103, July.
    5. Erola Pairo-Castineira & Sara Clohisey & Lucija Klaric & Andrew D. Bretherick & Konrad Rawlik & Dorota Pasko & Susan Walker & Nick Parkinson & Max Head Fourman & Clark D. Russell & James Furniss & Ann, 2021. "Genetic mechanisms of critical illness in COVID-19," Nature, Nature, vol. 591(7848), pages 92-98, March.
    6. Philip J. Law & Sonja I. Berndt & Helen E. Speedy & Nicola J. Camp & Georgina P. Sava & Christine F. Skibola & Amy Holroyd & Vijai Joseph & Nicola J. Sunter & Alexandra Nieters & Silvia Bea & Alain Mo, 2017. "Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    7. Toni M. Delorey & Carly G. K. Ziegler & Graham Heimberg & Rachelly Normand & Yiming Yang & Åsa Segerstolpe & Domenic Abbondanza & Stephen J. Fleming & Ayshwarya Subramanian & Daniel T. Montoro & Karth, 2021. "COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets," Nature, Nature, vol. 595(7865), pages 107-113, July.
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