A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways

Abstract

Publisher Copyright: © 2024 American Academy of Dermatology, Inc.Background: The contributions of genetic and environmental risk factors to hidradenitis suppurativa (HS) are both poorly understood. Objective: To identify sequence variants that associate with HS and determine the contribution of environmental risk factors and inflammatory diseases to HS pathogenesis. Methods: A genome-wide association meta-analysis of 4814 HS cases (Denmark: 1977; Iceland: 1266; Finland: 800; UK: 569; and US: 202) and 1.2 million controls, searching for sequence variants associated with HS. Results: We found 8 independent sequence variants associating with HS, 6 common and 2 rare (frequency <1%). Four associations point to candidate causal genes, NCSTN, PSENEN, WNT10A, and TMED10, that all map to the Notch and Wnt/β-catenin signaling pathways, involved in epidermal keratinization. Limitations: Limited racial diversity may prevent identification of sequence variants of particular importance in non-Caucasian populations. Conclusions: These findings demonstrate that genes and pathways involved in epidermal keratinization are the genetic backbone of HS pathology.Peer reviewe