Genome wide association study identifying genetic variants associated with atopic dermatitis in the All of Us Database

Qiang Zhang, BA 

Nicole Johnsen, BS 

Joshua Rivera, BS 

Frank Zhou, BA 

Area of Concentration: Basic, Clinical, & Translational Research 

Speciality: Dermatology 

Keywords: Atopic Dermatitis, Genetics 

Background: Atopic Dermatitis (AD), a prevalent inflammatory skin condition, is known to have complex polygenic associations. Twin studies estimate AD heritability at approximately 75%, with the filaggrin (FLG) gene's loss-of-function mutations (located on chromosome 1q21.3) being the most potent known genetic risk factor. Prior studies have identified up to 81 potential susceptible genetic loci and 202 unique variants linked to AD. Despite this knowledge, a substantial portion of the genetic risk for AD remains unexplored, particularly in minority populations.

Objective: Using the diverse All of Us NIH-funded database, we looked at genome wide association study data to provide valuable insight into the genetics of AD (case N = 2,907, control N = 242,481).

Methods: Statistical analysis employed logistic regression to describe the association of gene prevalence with AD, while correcting for covariates such as sex, ethnicity, age, and comorbidities.

Results: Our analysis demonstrated 564 statistically significant variants linked to AD, and reaffirmed numerous candidate gene associations present in the literature (such as FLG, FAR1, and GFAP). The most significant gene variant linked to AD with a p-value of 0.000131 was PKP1 (plakophilin 1), which plays a role in desmosomal cell-cell adhesion in epithelial tissues and is known to cause ectodermal dysplasia-skin fragility syndrome. To date, the association of PKP1 with AD has not been well described in the literature. Other significant variants have functions that impact skin barrier capability such as: collagen formation, immune response and inflammation, cell-cell adhesion, tight-junctions, and transcriptional regulation.

Conclusion: We hope that these genetic findings uncover promising targets for advancing therapeutic interventions and precision medicine.