Genome-wide cross-trait analysis of heterogeneous outcomes in early life atopic dermatitis

Pediatric atopic dermatitis exhibits substantial heterogeneity in presentation, course, and long-term outcomes resulting in distinct phenotypes. Yet, genetic studies of atopic dermatitis have focused on a single trait or outcome and thus may not fully reveal underlying genetic relationships.

To identify novel genetic associations with early-life atopic dermatitis traits and evaluate shared genetic architecture across heterogeneous quantitative outcomes using a genome-wide cross-trait approach.

Children (n = 601) participating in the Mechanisms in the Progression of Atopic Dermatitis to Asthma in Childhood were genotyped and association was performed for each of 12 traits. Pleiotropy analyses were used to organize genetically similar traits into Pleiotropic Groups. A principal components (composite) variable was generated for each pleiotropic group and another genetic association was performed.

Five novel genome-wide significant associations were identified with single traits: progression to additional atopic conditions, S100A8 lesional expression (2 associations), sensitization to food allergens, and sensitization to aeroallergens. When evaluating pleiotropy, the 12 traits organized into 4 pleiotropic groups. There were more shared gene associations among traits within a pleiotropic group than between (p = 1.5 × 10^-5). A novel genome-wide significant association was found with the Composite Variable from Pleiotropic Group 3.

Herein, we identify novel genetic associations with pediatric atopic dermatitis traits. Further, our findings reveal a novel opportunity for enhancing genetic discovery by leveraging multi-trait effects and provide new insights into atopic dermatitis traits with shared genetic etiologies.