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 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.
| Original language | English (US) |
|---|---|
| Article number | 1632 |
| Journal | Nature communications |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
ASJC Scopus subject areas
- General
- Physics and Astronomy(all)
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
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In: Nature communications, Vol. 13, No. 1, 1632, 12.2022.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Sajuthi, Satria P.
AU - Everman, Jamie L.
AU - Jackson, Nathan D.
AU - Saef, Benjamin
AU - Rios, Cydney L.
AU - Moore, Camille M.
AU - Mak, Angel C.Y.
AU - Eng, Celeste
AU - Fairbanks-Mahnke, Ana
AU - Salazar, Sandra
AU - Elhawary, Jennifer
AU - Huntsman, Scott
AU - Medina, Vivian
AU - Nickerson, Deborah A.
AU - Germer, Soren
AU - Zody, Michael C.
AU - Abecasis, Gonçalo
AU - Kang, Hyun Min
AU - Rice, Kenneth M.
AU - Kumar, Rajesh
AU - Zaitlen, Noah A.
AU - Oh, Sam
AU - Rodríguez-Santana, José
AU - Burchard, Esteban G.
AU - Seibold, Max A.
N1 - Funding Information: This work was supported by NIH grants (MAS) R01 HL135156, R01 MD010443, R01 HL128439, P01 HL132821, P01 HL107202, R01 HL117004, and DOD Grant W81WH-16-2-0018. The Genes-Environments and Admixture in Latino Americans (GALA II) Study and E.G.B. were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, the Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute (NHLBI) [R01HL117004, R01HL128439, R01HL135156, X01HL134589]; the National Institute of Environmental Health Sciences [R01ES015794]; the National Institute on Minority Health and Health Disparities (NIMHD) [P60MD006902, R01MD010443], the National Human Genome Research Institute [U01HG009080] and the Tobacco-Related Disease Research Program [24RT-0025, 27IR-0030]. Burchard NIH Support: R01 128439, R01 HL141992, R01 HL141845. Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for NHLBI TOPMed: Gene-Environment, Admixture and Latino Asthmatics Study (phs000920) was performed at the New York Genome Center (3R01HL117004-02S3) and the University of Washington Northwest Genomics Center (HHSN268201600032I). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1, U01HL-120393, contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. WGS of part of GALA II was performed by New York Genome Center under The Centers for Common Disease Genomics of the Genome Sequencing Program (GSP) Grant (UM1 HG008901). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. GSP is funded by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and the National Eye Institute. We wish to acknowledge the following GALA II study collaborators: Shannon Thyne, UCSF; Harold J. Farber, Texas Children’s Hospital; Denise Serebrisky, Jacobi Medical Center; Rajesh Kumar, Lurie Children’s Hospital of Chicago; Emerita Brigino-Buenaventura, Kaiser Permanente; Michael A. LeNoir, Bay Area Pediatrics; Kelley Meade, UCSF Benioff Children’s Hospital, Oakland; William Rodríguez-Cintrón, VA Hospital, Puerto Rico; Pedro C. Ávila, Northwestern University; Jose R. Rodríguez-Santana, Centro de Neumología Pediátrica; Luisa N. Borrell, City University of New York; Adam Davis, UCSF Benioff Children’s Hospital, Oakland; Saunak Sen, University of Tennessee. The authors acknowledge the families and patients for their participation and thank the numerous health care providers and community clinics for their support and participation in GALA II. In particular, the authors thank the recruiters who obtained the data: Duanny Alva, MD; Gaby Ayala-Rodríguez; Lisa Caine, RT; Elizabeth Castellanos; Jaime Colón; Denise DeJesus; Blanca López; Brenda López, MD; Louis Martos; Vivian Medina; Juana Olivo; Mario Peralta; Esther Pomares, MD; Jihan Quraishi; Johanna Rodríguez; Shahdad Saeedi; Dean Soto; and Ana Taveras. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: This work was supported by NIH grants (MAS) R01 HL135156, R01 MD010443, R01 HL128439, P01 HL132821, P01 HL107202, R01 HL117004, and DOD Grant W81WH-16-2-0018. The Genes-Environments and Admixture in Latino Americans (GALA II) Study and E.G.B. were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, the Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute (NHLBI) [R01HL117004, R01HL128439, R01HL135156, X01HL134589]; the National Institute of Environmental Health Sciences [R01ES015794]; the National Institute on Minority Health and Health Disparities (NIMHD) [P60MD006902, R01MD010443], the National Human Genome Research Institute [U01HG009080] and the Tobacco-Related Disease Research Program [24RT-0025, 27IR-0030]. Burchard NIH Support: R01 128439, R01 HL141992, R01 HL141845. Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for NHLBI TOPMed: Gene-Environment, Admixture and Latino Asthmatics Study (phs000920) was performed at the New York Genome Center (3R01HL117004-02S3) and the University of Washington Northwest Genomics Center (HHSN268201600032I). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1, U01HL-120393, contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. WGS of part of GALA II was performed by New York Genome Center under The Centers for Common Disease Genomics of the Genome Sequencing Program (GSP) Grant (UM1 HG008901). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. GSP is funded by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and the National Eye Institute. We wish to acknowledge the following GALA II study collaborators: Shannon Thyne, UCSF; Harold J. Farber, Texas Children’s Hospital; Denise Serebrisky, Jacobi Medical Center; Rajesh Kumar, Lurie Children’s Hospital of Chicago; Emerita Brigino-Buenaventura, Kaiser Permanente; Michael A. LeNoir, Bay Area Pediatrics; Kelley Meade, UCSF Benioff Children’s Hospital, Oakland; William Rodríguez-Cintrón, VA Hospital, Puerto Rico; Pedro C. Ávila, Northwestern University; Jose R. Rodríguez-Santana, Centro de Neumología Pediátrica; Luisa N. Borrell, City University of New York; Adam Davis, UCSF Benioff Children’s Hospital, Oakland; Saunak Sen, University of Tennessee. The authors acknowledge the families and patients for their participation and thank the numerous health care providers and community clinics for their support and participation in GALA II. In particular, the authors thank the recruiters who obtained the data: Duanny Alva, MD; Gaby Ayala-Rodríguez; Lisa Caine, RT; Elizabeth Castellanos; Jaime Colón; Denise DeJesus; Blanca López; Brenda López, MD; Louis Martos; Vivian Medina; Juana Olivo; Mario Peralta; Esther Pomares, MD; Jihan Quraishi; Johanna Rodríguez; Shahdad Saeedi; Dean Soto; and Ana Taveras. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127292952&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127292952&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-28973-7
DO - 10.1038/s41467-022-28973-7
M3 - Article
C2 - 35347136
AN - SCOPUS:85127292952
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1632
ER -