Discerning asthma endotypes through comorbidity mapping
- PMID: 36344522
- PMCID: PMC9640644
- DOI: 10.1038/s41467-022-33628-8
Discerning asthma endotypes through comorbidity mapping
Abstract
Asthma is a heterogeneous, complex syndrome, and identifying asthma endotypes has been challenging. We hypothesize that distinct endotypes of asthma arise in disparate genetic variation and life-time environmental exposure backgrounds, and that disease comorbidity patterns serve as a surrogate for such genetic and exposure variations. Here, we computationally discover 22 distinct comorbid disease patterns among individuals with asthma (asthma comorbidity subgroups) using diagnosis records for >151 M US residents, and re-identify 11 of the 22 subgroups in the much smaller UK Biobank. GWASs to discern asthma risk loci for individuals within each subgroup and in all subgroups combined reveal 109 independent risk loci, of which 52 are replicated in multi-ancestry meta-analysis across different ethnicity subsamples in UK Biobank, US BioVU, and BioBank Japan. Fourteen loci confer asthma risk in multiple subgroups and in all subgroups combined. Importantly, another six loci confer asthma risk in only one subgroup. The strength of association between asthma and each of 44 health-related phenotypes also varies dramatically across subgroups. This work reveals subpopulations of asthma patients distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes, and so reveals different asthma endotypes.
© 2022. The Author(s).
Conflict of interest statement
J.S. reports grants from NIH, during the conduct of the study; grants from NIH, personal fees from PulmOne Advanced Medical Devices, Ltd, Israel, personal fees and non-financial support from Regeneron/Sanofi-Genzyme, grants from Chicago Biomedical Consortium Accelerator Network, outside the submitted work; in addition, J.S. has US Patents #6,090,618, #6,114,311, #6,284,743, #6,291,211, #6,297,221, #6,331,527, #7,169,764 issued, and two patent applications (WO2020206109 and WO2020206118) pending. The other authors declare no competing interests. S.W. reports grants from NIH during the conduct of the study; grants from NIH and personal fees from Regeneron/Sanofi-Genzyme and Astra-Zeneca, outside the submitted work.
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References
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- CDC.gov. CDC - Asthma - Data and Surveillance - Asthma Surveillance Data. Available at: http://www.cdc.gov/asthma/asthmadata.htm [Accessed 15 September 2019] (2018).
-
- Bouzigon E, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N. Engl. J. Med. 2008;359:1985–1994. - PubMed
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