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

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 95 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.

Nature Communications volume 13, Article number: 1632 (2022)


Other Contributors

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, Scott Huntsman, Vivian Medina, Deborah A. Nickerson, Soren Germer, Michael C. Zody, Gonçalo Abecasis, Hyun Min Kang, Kenneth M. Rice, Rajesh Kumar, Noah A. Zaitlen, Sam Oh, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, José Rodríguez-Santana, Esteban G. Burchard & Max A. Seibold