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

R Kjærsgaard Andersen; L Stefansdottir; P Theut Riis; Gh Halldorsson; E Ferkingstad; A Oddsson; G B Walters; Thorunn A Olafsdottir; G Rutsdottir; C Zachariae; S F Thomsen; T Brodersen; K M Dinh; K U Knowlton; S Knight; L D Nadauld; K Banasik; S Brunak; T F Hansen; H Hjalgrim; E Sørensen; C Mikkelsen; H Ullum; M Nyegaard; M T Bruun; C Erikstrup; S R Ostrowski; L Eidsmo; D M L Saunte; B Sigurgeirsson; K B Orvar; J Saemundsdottir; P Melsted; G L Norddahl; P Sulem; H Stefansson; H Holm; D Gudbjartsson; G Thorleifsson; I Jonsdottir; O B V Pedersen; G B E Jemec; K Stefansson

doi:10.1016/j.jaad.2024.11.050

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

J Am Acad Dermatol. 2024 Dec 5:S0190-9622(24)03292-4. doi: 10.1016/j.jaad.2024.11.050. Online ahead of print.

Authors

R Kjærsgaard Andersen¹, L Stefansdottir², P Theut Riis³, Gh Halldorsson⁴, E Ferkingstad², A Oddsson², G B Walters², Thorunn A Olafsdottir⁵, G Rutsdottir², C Zachariae⁶, S F Thomsen⁷, T Brodersen⁸, K M Dinh⁹, K U Knowlton¹⁰, S Knight¹⁰, L D Nadauld¹¹, K Banasik¹², S Brunak¹², T F Hansen¹³, H Hjalgrim¹⁴, E Sørensen¹⁵, C Mikkelsen¹⁶, H Ullum¹⁷, M Nyegaard¹⁸, M T Bruun¹⁹, C Erikstrup²⁰, S R Ostrowski²¹, L Eidsmo²², D M L Saunte²³, B Sigurgeirsson²⁴, K B Orvar²⁵, J Saemundsdottir², P Melsted⁴, G L Norddahl², P Sulem², H Stefansson², H Holm², D Gudbjartsson⁴, G Thorleifsson², I Jonsdottir⁵, O B V Pedersen²⁶, G B E Jemec²³, K Stefansson²⁷

Affiliations

¹ Department of Dermatology, Zealand University Hospital, Roskilde, Denmark; Department of Immunology and Microbiology, Leo Foundation Skin Immunology Research Center, University of Copenhagen, Denmark. Electronic address: rune.andersen@sund.ku.dk.
² deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
³ Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.
⁴ deCODE genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
⁵ deCODE genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
⁶ Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark.
⁷ Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
⁸ Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
⁹ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
¹⁰ Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT, USA; University of Utah, School of Medicine, Salt Lake City, UT, USA.
¹¹ Precision Genomics, Intermountain Healthcare, Saint George, UT, USA.
¹² Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Danish Headache Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet-Glostrup, Copenhagen, Denmark.
¹⁴ Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Dept. of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Denmark.
¹⁵ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
¹⁶ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, Copenhagen University, Copenhagen, Denmark.
¹⁷ Statens Serum Institut, Copenhagen, Denmark.
¹⁸ Department of Health Science and Technology, Aalborg University, Gistrup, Denmark.
¹⁹ Clinical Immunology Research Unit, Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.
²⁰ Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²¹ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Dept. of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Denmark.
²² Department of Immunology and Microbiology, Leo Foundation Skin Immunology Research Center, University of Copenhagen, Denmark.
²³ Department of Dermatology, Zealand University Hospital, Roskilde, Denmark; Dept. of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Denmark.
²⁴ Department of Dermatology, Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
²⁵ Landspitali, the National University Hospital of Iceland, Department of Medicine, Reykjavík, Iceland.
²⁶ Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Dept. of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Denmark.
²⁷ deCODE genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavík, Iceland. Electronic address: kstefans@decode.is.

PMID: 39645042
DOI: 10.1016/j.jaad.2024.11.050

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 4,814 HS cases (Denmark: 1,977; Iceland: 1,266; 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.

Keywords: GWAS; Genome-wide association study; Hidradenitis suppurativa; NOTCH; Notch signaling; WNT; Wnt signaling; causality; genetics; inheritance; pathway analysis; γ-secretase.