Sex and Obesity Stratified Asthma GWAS in African and European Ancestry Populations

Background: Biologically distinct asthma subgroups may obscure genetic effects when analyzed as a single phenotype. We examined whether asthma susceptibility signals are shared, heterogeneous, or stratum-specific across ancestry, obesity status, and sex. Methods: We performed ancestry-specific GWAS meta-analyses in African ancestry participants (9,965 asthma cases; 37,391 controls) and European ancestry participants (6,074 cases; 116,255 controls), followed by obesity- and sex-stratified analyses. Analyses used imputed dosages and fixed-effect meta-analysis within ancestry. Results: Stratification detected asthma association signals that were less apparent in the combined phenotype. Shared cross-ancestry loci implicated epithelial antiviral susceptibility and immune regulation, represented by signals near CDHR3 and FOXO1. An ancestry-heterogeneous signal at the 17q21 locus, harboring ORMDL3/GSDMB, supported population-dependent effects at an epithelial inflammatory locus. Obesity stratification mapped the genome-wide significant burden to asthma without obesity. Sex stratification detected genome-wide significant signals in AFR females with asthma and obesity and in both sex strata with asthma without obesity, with the strongest signal burden in EU females without obesity. Conclusions: Asthma genetic architecture differed by ancestry, obesity status, and sex. Stratified analyses identified group-specific susceptibility related to epithelial and immune regulation, airway inflammation, remodeling, and neural signaling, supporting precision approaches to asthma.