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
Rune Kjærsgaard Andersen, Lilja Stefánsdóttir, Peter Theut Riis, Gísli H. Halldórsson, Egil Ferkingstad, Ásmundur Oddsson, G. Bragi Walters, Thorunn A. Olafsdottir, Gudrun Rutsdottir, Claus Zachariae, Simon Francis Thomsen, Thortsen Brodersen, Khoa Manh Dinh, Kirk U. Knowlton, Stacey Knight, Lincoln Nadauld, Karina Banasik, Søren Brunak, Thomas Folkmann Hansen, Henrik Hjalgrim, Erik Sørensen, Chirstina Mikkelsen, Henrik Ullum, Mette Nyegaard, Mie Topholm Bruun, Christian Erikstrup, Sisse Rye Ostrowski, Liv Eidsmo, Ditte Marie Lindhardt Saunte, Bárður Sigurgeirsson, Kjartar B Orvar, Jona Saemundsdottir, Páll Melsted, Gudmundur L. Norddahl, Patrick Sulem, Hreinn Stefánsson, Hilma Hólm, Daníel F. Guðbjartsson, Gudmar Thorleifsson, Ingileif Jónsdóttir, Ole Birger Pedersen, Gregor B. E. Jemec, Kari Stefansson
Abstract
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.