Document Type
Article
Publication Date
2023
DOI
10.1038/s41588-023-01314-0
Publication Title
Nature Genetics
Volume
55
Issue
3
Pages
410-428
Abstract
Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Rights
This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Data Availability
Article states: Genome-wide summary statistics for the multi-ancestry meta-analysis are available at the GWAS Catalog (https://www.ebi.ac.uk/gwas/) under the accession codes GCST90244092, GCST90244093, GCST90244094 and GCST90244095.
Original Publication Citation
Shrine, N., Izquierdo, A. G., Chen, J., Packer, R., Hall, R. J., Guyatt, A. L., Batini, C., Thompson, R. J., Pavuluri, C., Malik, V., Hobbs, B. D., Moll, M., Kim, W., Tal-Singer, R., Bakke, P., Fawcett, K. A., John, C., Coley, K., Piga, N. N., . . . Tobin, M. D. (2023). Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Nature Genetics, 55(3), 410-428. https://doi.org/10.1038/s41588-023-01314-0
ORCID
0000-0003-1230-5162 (Sikdar)
Repository Citation
Shrine, Nick; Izquierdo, Abril G.; Chen, Jing; Packer, Richard; Hall, Robert J.; Guyatt, Anna L.; Batini, Chiara; Thompson, Rebecca J.; Puvuluri, Chandan; Malik, Vidhi; Hobbs, Brian D.; Moll, Matthew; Kim, Wonji; Tal-Singer, Ruth; Bakke, Per; Fawcett, Katherine A.; John, Catherine; Coley, Kayesha; Piga, Noemi Nicole; Sikdar, Sinjini; Tobin, Martin D.; and Et al., "Multi-Ancestry Genome-Wide Association Analyses Improve Resolution of Genes and Pathways Influencing Lung Function and Chronic Obstructive Pulmonary Disease Risk" (2023). Mathematics & Statistics Faculty Publications. 233.
https://digitalcommons.odu.edu/mathstat_fac_pubs/233
Included in
Cardiovascular Diseases Commons, Cardiovascular System Commons, Genetics and Genomics Commons, Genetic Structures Commons
Comments
Correction to article available at: https://doi.org/10.1038/s41588-023-01314-0
Correction also included as an additional file.