Genomic structural equation modeling dissects Th2-mediated and Th2-independent genetic pathways of the atopic march

Atopic dermatitis (AD) and childhood-onset asthma (COA) share genetic susceptibility, but the contribution captured by type 2 (Th2) inflammatory traits and the residual sharing are incompletely resolved. The atopic march is one clinical trajectory rather than a universal sequence.

We used genomic structural equation modeling (Genomic SEM) to examine genetic covariance among AD, COA, blood eosinophil count, and IgE-related protein abundance. A latent Th2 factor defined two model-based components, termed Th2-mediated and Th2-independent. Component GWAS, MAGMA/FOCUS, single-cell scoring, spatial mapping, Mendelian randomization (MR), and protein-QTL SMR informed candidate prioritization. Functional follow-up compared HSPA1A and HSPA1B knockdown, combined knockdown, and pharmacological IKK inhibition.

Component-based analyses prioritized 121 Th2-mediated and 204 Th2-independent genes, including 71 shared genes. Alternative genetic-covariance structures provided a transparent comparison of AD-to-COA representations. MR estimates were evaluated across complementary sensitivity estimators, and HSPA1A/HSPA1B SMR associations were interpreted together with their HEIDI heterogeneity results. Lesional-skin spatial contrasts attenuated after adjustment for an epidermal marker-expression score. HSPA1B knockdown increased inflammatory outputs, with larger changes after combined HSPA1A/HSPA1B knockdown, while BMS-345541 attenuated these changes.

The Th2-based genetic decomposition provides a candidate map for allergic-disease biology, including HSPA1B-associated epithelial stress responses. The framework prioritizes testable biology across inherited susceptibility and epithelial stress responses, with longitudinal mediation, complete independence from type 2 biology, and skin-to-airway propagation reserved for direct clinical and mechanistic testing.