PROJECT SUMMARY/ABSTRACT Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that has a devastating effect on quality of life. HS affects up to 1.2% of people and disproportionately affects women and Black people. The age of onset is typically in adolescence/young adulthood and symptoms persist for decades. More than half of patients have affected family members, consistent with a strong genetic contribution to HS. Variants implicated in familial cases of HS have been reported in four genes, three of which encode subunits of the γ-secretase complex, but these likely affect less than 5% of patients with HS, raising the question: what other variants may be at play? In our recent genome-wide association study (GWAS) of 760 patients and meta-analysis with additional cohorts, we identified significant risk loci near SOX9 and KLF5, which play important roles in follicular and epidermal maintenance, wound healing, and inflammation. We hypothesize that larger sample sizes will identify additional significant risk loci that will substantially improve our understanding of disease pathogenesis and identify potential treatment targets. We further hypothesize that dysregulated SOX9 and KLF5 expression will be found in the hair follicles, epidermis, and cutaneous tunnels in skin from HS patients. In this study, we propose to build upon our recent GWAS to examine the genetic basis of HS in an expanded cohort of 2,000 diverse patients with HS at the University of North Carolina at Chapel Hill. We continue to recruit participants from one of the highest volume HS subspecialty clinics in the country. Approximately 50% of our cohort is composed of Black patients, and we will examine potential differences in the genetic architecture based on ancestry, sex, and phenotypic diversity. We also will perform GWAS in the All of Us cohort and meta-analyze GWAS results with the FinnGen, UK Biobank, and BioVU biobanks, and other cohorts as described in the research plan. This meta-analysis will include more than 12,000 total subjects. Identifying genetic variants that show evidence for association with HS disease status will provide candidate genes for further validation and biological study to develop new treatments and possibly prevent disease. At the recently discovered GWAS loci near SOX9 and KLF5, we will analyze gene expression patterns in HS-affected tissue using RNA-seq and immunohistochemistry. To identify candidate genes for new loci, we will analyze transcriptome data to identify variants associated with both HS and gene expression and integrate with existing chromatin data. To identify HS risk variants that affect gene expression, we will evaluate skin cell transcriptome and epigenome data and perform reporter assays in keratinocytes. By identifying dysregulated gene expression patterns in the epidermis, hair follicles, and cutaneous tunnels of HS-affected tissue, we will learn how risk variants contribute to follicular disruption, inflammatory re...