The Genetics of Hidradenitis Suppurativa

Abstract: Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin disease characterized by painful nodules, abscesses, tunnels, and scarring, with substantial clinical and psychological burden. Genetic studies have revealed that HS has a complex and heterogeneous architecture, encompassing rare monogenic mutations, intermediate-frequency variants, and polygenic risk distributed across multiple loci. Familial aggregation, twin studies, and genome-wide association studies collectively demonstrate that inherited factors contribute substantially to disease susceptibility. Different genetic profiles influence disease onset, severity, and clinical phenotype. Monogenic γ-secretase mutations are associated with early-onset, severe, and extensive disease, whereas polygenic risk shapes heterogeneous presentations and may modify disease trajectory. Genetic variants implicated in HS also intersect with systemic comorbidities including inflammatory bowel disease, spondyloarthritis, coronary artery disease, and diabetes, highlighting shared pathogenic pathways. Mechanistic insights indicate that dysregulated Notch and Wnt/β-catenin signaling; keratinization and epithelial differentiation are central drivers of genotype-informed clinical trials. Despite advances, many variants remain uncharacterized, and polygenic risk scores currently have limited predictive power. Integration of genetic findings with clinical, environmental, and longitudinal phenotypic data is therefore essential to inform risk assessment, patient stratification, and early intervention. This review synthesizes current knowledge on HS genetics, emphasizing genotype-phenotype correlations, comorbidity associations, and translated opportunities, and outlines research priorities needed to advance toward precision medicine approaches for HS. Keywords: inflammatory skin disease, polygenic risk, γ-secretase mutations, genotype–phenotype correlation, notch signaling, precision medicine