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. 2025 Sep 12:S0091-6749(25)00945-5.
doi: 10.1016/j.jaci.2025.07.036. Online ahead of print.

Unraveling shared genetics across asthma subtypes and 81 asthma-related traits

Raphaël Vernet  1 , Christophe Linhard  1 , Anja Estermann  1 , Yuka Suzuki  2 , Florence Demenais  1 , Hugues Aschard  2 , Hanna Julienne  3 , Emmanuelle Bouzigon  4
Affiliations
Free article

Unraveling shared genetics across asthma subtypes and 81 asthma-related traits

Raphaël Vernet et al. J Allergy Clin Immunol. .
Free article

Abstract

Background: Asthma presents clinical and biological heterogeneity.

Objective: We sought to better understand asthma heterogeneity by investigating the shared genetics between various asthma subtypes and a large number of biological and physiologic traits involved in asthma pathophysiology.

Methods: We built a harmonized comprehensive database of 254 full genome-wide association study summary statistics datasets on asthma, asthma subtypes and 81 asthma-related traits (blood cells and molecular, anthropometric, and lung function traits). We enriched this database by performing meta-analyses for asthma-related traits reported in ≥2 studies. Then we identified shared genome-wide significant loci and estimated genetic overlaps and correlations (rg) between asthma subtypes and asthma-related traits by MiXeR software and linkage disequilibrium score regression.

Results: Overall, asthma-associated loci were more pleiotropic than non-asthma-associated loci (median of shared traits, 4 vs 1, P = 1.3 × 10-36). Childhood-onset and moderate-to-severe asthma had higher SNP heritability (h2SNP ± standard error [SE], 0.27 ± 0.004 and 0.16 ± 0.02, respectively) than adult-onset asthma (0.08 ± 0.002) and asthma ever (0.06 ± 0.001). All asthma subtypes showed significant rg with eosinophils and IgE levels (0.24 ≤ rg ≤ 0.40, 5.1 × 10-14 ≤ P ≤ .04), with childhood-onset asthma sharing 94% of "causal" variants with IgE, whereas other asthma subtypes shared <60%. Adult-onset asthma showed significant rg and shared a substantial amount of causal variants with adult body mass index (rg = 0.26, P < .007; shared variants, 84%) and forced expiratory volume in 1 second (rg = -0.36, P < 7.7 × 10-10; shared variants, 95%). Finally, moderate-to-severe asthma was characterized by a significant rg with hepatocyte growth factor levels (rg = 0.38, P = 6 × 10-4), a potential biomarker of lung injury.

Conclusion: Common and specific genetic architectures underlie different asthma subtypes and can help us understand the pathophysiologic mechanisms underlying asthma heterogeneity.

Keywords: Asthma; GWAS summary statistics; asthma-related traits; genetic correlation; genetic heterogeneity.

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Conflict of interest statement

Disclosure statement Supported by the Agence Nationale de la Recherche (ANR-20-CE36-0009 GenCAST) and a Université Paris Cité Doctoral Fellowship. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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