Project Summary Hidradenitis suppurativa (HS) is a chronic, debilitating, inflammatory skin condition characterized by painful abscesses and lesions in the intertriginous areas. HS affects all races; however, racial disparities exist with increased prevalence, severity, delay in diagnosis, and dermatologic care in Black/African American and Hispanic/Latino HS patients compared to White counterparts. Despite these differences, contributing factors to these disparities in HS remain understudied. Although multiple studies have established the genetic components of HS, only one large-scale genetic study on HS susceptibility has been published. Our main hypothesis is that novel and rare coding-sequence variants missing in the current GWAS studies contribute to the differences in HS risk seen among Black/African American and Hispanics/Latino patients. Focusing on coding sequence variants is important since many disease-predisposing SNPs reside in the exome. Using whole-exome sequencing (WES) to comprehensively assess the associations of rare and common coding variants with HS, we will leverage data from our unique cohorts and other existing genetic resources including the All of Us and UK biobank data to evaluate our hypothesis through the following specific aims. In Aim 1 we will perform WES family and case-control analyses to Identify specific coding sequence variants associated with HS in different racial/ethnic groups (Black/AA, Hispanic/Latino, and White individuals). In Aim 2, we will study the impact of HS-associated coding-sequence variants on cellular biology by performing bioinformatics and multi-omics analyses with gain- and/or loss-of-function of candidate genes with variants. Insights into the novel and rare coding sequence variations associated with HS risk and knowledge of racial disparities in HS genetic risk will be gained through the successful completion of this proposal, which may lead to the development of new HS therapeutics.