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Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

Author

Listed:
  • Satria P. Sajuthi

    (National Jewish Health)

  • Jamie L. Everman

    (National Jewish Health)

  • Nathan D. Jackson

    (National Jewish Health)

  • Benjamin Saef

    (National Jewish Health)

  • Cydney L. Rios

    (National Jewish Health)

  • Camille M. Moore

    (National Jewish Health
    National Jewish Health
    University of Colorado)

  • Angel C. Y. Mak

    (University of California-San Francisco)

  • Celeste Eng

    (University of California-San Francisco)

  • Ana Fairbanks-Mahnke

    (National Jewish Health)

  • Sandra Salazar

    (University of California-San Francisco)

  • Jennifer Elhawary

    (University of California-San Francisco)

  • Scott Huntsman

    (University of California-San Francisco)

  • Vivian Medina

    (Centro de Neumología Pediátrica)

  • Deborah A. Nickerson

    (University of Washington)

  • Soren Germer

    (New York Genome Center)

  • Michael C. Zody

    (New York Genome Center)

  • Gonçalo Abecasis

    (University of Michigan)

  • Hyun Min Kang

    (University of Michigan)

  • Kenneth M. Rice

    (University of Washington)

  • Rajesh Kumar

    (Northwestern University)

  • Noah A. Zaitlen

    (University of California Los Angeles)

  • Sam Oh

    (University of California-San Francisco)

  • José Rodríguez-Santana

    (Centro de Neumología Pediátrica)

  • Esteban G. Burchard

    (University of California-San Francisco
    University of California-San Francisco)

  • Max A. Seibold

    (National Jewish Health
    National Jewish Health
    University of Colorado School of Medicine)

Abstract

To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 102 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology.

Suggested Citation

  • Satria P. Sajuthi & Jamie L. Everman & Nathan D. Jackson & Benjamin Saef & Cydney L. Rios & Camille M. Moore & Angel C. Y. Mak & Celeste Eng & Ana Fairbanks-Mahnke & Sandra Salazar & Jennifer Elhawary, 2022. "Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28973-7
    DOI: 10.1038/s41467-022-28973-7
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    References listed on IDEAS

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    2. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    3. Bates, Douglas & Mächler, Martin & Bolker, Ben & Walker, Steve, 2015. "Fitting Linear Mixed-Effects Models Using lme4," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 67(i01).
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    Cited by:

    1. Jamie L. Everman & Satria P. Sajuthi & Maude A. Liegeois & Nathan D. Jackson & Erik H. Collet & Michael C. Peters & Maurizio Chioccioli & Camille M. Moore & Bhavika B. Patel & Nathan Dyjack & Roger Po, 2024. "A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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