Project summary Hidradenitis suppurativa (HS) is an underrecognized common, immune-mediated skin disease characterized by inflammatory nodules, abscesses, and sinus tracts in the groin, buttocks, and axillae leading to devasting physical and emotional morbidity. HS significantly affects European Americans and minorities such as African-Americans, Asians, and Latinos. Treatments for HS are poor, with only a single FDA-approved therapy available. The paucity of treatments is driven by a profound lack of understanding of HS pathogenesis, particularly with respect to the genetic pathways involved. In this application, we utilize a variety of innovative approaches to address this significant gap. First, we perform a genome-wide association study (GWAS) in European, African American, and Asian HS cases and healthy controls. Second, we perform trans-ethnic genome wide meta-analysis to identify shared and distinct genetic risk factors. Third, we will perform multi-racial spatial transcriptomics and proteomics of HS skin to elucidate cell-cell interactions, and further identify causal GWAS variants through luciferase reporter assays. Together, these studies will advance our knowledge of the genetic architecture and immunobiology of HS in different racial populations and identify new biologic pathways that can be therapeutically targeted.