Enhancer RNA transcription pinpoints functional genetic variants linked to asthma

Sarah K. Sasse, Amber Dahlin, Lynn Sanford, Margaret A. Gruca, Arnav Gupta, Fabienne Gally, Ann Chen Wu, Carlos Iribarren, Robin D. Dowell, Scott T. Weiss and Anthony N. Gerber ()
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Sarah K. Sasse: National Jewish Health
Amber Dahlin: Brigham and Women’s Hospital and Harvard Medical School
Lynn Sanford: University of Colorado
Margaret A. Gruca: University of Colorado
Arnav Gupta: National Jewish Health
Fabienne Gally: University of Colorado
Ann Chen Wu: Harvard Medical School and Harvard Pilgrim Health Care Institute
Carlos Iribarren: Kaiser Permanente
Robin D. Dowell: University of Colorado
Scott T. Weiss: Brigham and Women’s Hospital and Harvard Medical School
Anthony N. Gerber: National Jewish Health

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Bidirectional enhancer RNA (eRNA) transcription is a widespread response to environmental signals and glucocorticoids. We investigated whether single nucleotide polymorphisms (SNPs) within dynamically regulated eRNA-transcribing regions contribute to genetic variation in asthma. Through applying multivariate regression modeling with permutation-based significance thresholding to a large clinical cohort, we identified novel associations between asthma and 35 SNPs located in eRNA-transcribing regions implicated in regulating cellular processes relevant to asthma, including rs258760 (mean allele frequency = 0.34, asthma odds ratio = 0.95; P = 5.04E-03). We show that rs258760 disrupts an active aryl hydrocarbon receptor (AHR) response element linked to transcriptional regulation of the glucocorticoid receptor gene by AHR ligands, which are commonly found in combusted air pollution. The role of rs258760 as a protective variant for asthma was independently validated using UK Biobank data. Our findings establish eRNA signatures as a tool for discovery of functional genetic variants and define a novel association between air pollution, glucocorticoid signaling and asthma.

Date: 2025
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DOI: 10.1038/s41467-025-57693-x

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