PROJECT SUMMARY/ABSTRACT Hidradenitis suppurativa (HS) is a chronic, painful, severe, inflammatory skin disease that has a devastating effect on patient quality of life. HS occurs in up to 0.5% of the general population, and the incidence has continued to increase over the last decade. Previous studies characterizing cohorts of HS patients have reported family history in 35-38% of patients, and 57% of our patients report an affected first or second degree relative. While HS affects individuals of all ancestries, it appears to disproportionally affect women and African- Americans (AA). The age of onset that is typically in adolescence/young adulthood (ages 15-25 years old) and symptoms continue throughout much of life. To date, genetic variants that may cause HS have been described in 27 families and 15 sporadic cases, but in follow-up screening studies, pathogenic genetic variants were detected in only 5 of 21 families and 2 of 68 patients with sporadic cases of HS. Genetic variants implicated in autoinflammation, abnormal follicular differentiation, and HS have been reported in four genes, including three genes encoding subunits of the gamma-secretase complex. However, the familial recurrence risk of HS and genetic contributions to HS are poorly understood for most patients. We hypothesize that systematic examination of the genetic contributions to HS will lead to the identification of genes and pathogenic, inflammatory pathways involved in disease onset and progression. In this study, we propose to examine the genetic basis of HS in a new cohort of 700 HS patients. Participants are being recruited from one of the largest HS populations in the country by chair of the North American HS Guidelines Committee who has experience with clinical trials for HS. At the time of re-submission, we have already collected clinical data, family history, and DNA specimens for 561 HS patients, ~50% African American and ~80% female. We aim to recruit at least 700 patients during the R21 funding period. We will characterize the distribution of disease severity and calculate sibling relative risk, as a measure of familial aggregation, and identify differences in risk based on age, sex, and ethnicity. To perform an unbiased search for new genetic variants associated with HS, we will perform a genome-wide association study (GWAS). For this analysis, we will make use of established methods for case-control matching and the extensive genome-wide sequence data available from the Trans-Omics for Precision Medicine (TOPMed) project and Genome Sequencing Project (GSP) to appropriately select controls. Identification of genetic variants that show evidence for association with HS disease status will provide target variants and candidate genes for further validation and biological study to detect new treatments and possibly prevention of disease.