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

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 HjalgrimE 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^*

^*Corresponding author for this work

11 Citations (Scopus)

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.

Original language	English
Journal	Journal of the American Academy of Dermatology
Volume	92
Issue number	4
Pages (from-to)	761-772
Number of pages	12
ISSN	0190-9622
DOIs	https://doi.org/10.1016/j.jaad.2024.11.050
Publication status	Published - Apr 2025

Keywords

Amyloid Precursor Protein Secretases/genetics
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Hidradenitis Suppurativa/genetics
Humans
Male
Membrane Glycoproteins
Polymorphism, Single Nucleotide
Receptors, Notch/genetics
Wnt Proteins/genetics
Wnt Signaling Pathway/genetics
GWAS
NOTCH
inheritance
hidradenitis suppurativa
pathway analysis
causality
Wnt signaling
genetics
Notch signaling
genome-wide association study
WNT
γ-secretase

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Andersen, R. K., Stefansdottir, L., Riis, P. T., Halldorsson, G., Ferkingstad, E., Oddsson, A., Walters, G. B., Olafsdottir, T. A., Rutsdottir, G., Zachariae, C., Thomsen, S. F., Brodersen, T., Dinh, K. M., Knowlton, K. U., Knight, S., Nadauld, L. D., Banasik, K., Brunak, S., Hansen, T. F., ... Stefansson, K. (2025). 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. Journal of the American Academy of Dermatology, 92(4), 761-772. https://doi.org/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. / Andersen, R Kjærsgaard; Stefansdottir, L; Riis, P Theut et al.
In: Journal of the American Academy of Dermatology, Vol. 92, No. 4, 04.2025, p. 761-772.

Research output: Contribution to journal › Journal article › Research › peer-review

Andersen, RK, Stefansdottir, L, Riis, PT, Halldorsson, G, Ferkingstad, E, Oddsson, A, Walters, GB, Olafsdottir, TA, Rutsdottir, G, Zachariae, C , Thomsen, SF, Brodersen, T, Dinh, KM, Knowlton, KU, Knight, S, Nadauld, LD, Banasik, K, Brunak, S, Hansen, TF, Hjalgrim, H, Sørensen, E , Mikkelsen, C, Ullum, H, Nyegaard, M, Bruun, MT, Erikstrup, C, Ostrowski, SR, Eidsmo, L, Saunte, DML, Sigurgeirsson, B, Orvar, KB, Saemundsdottir, J, Melsted, P, Norddahl, GL, Sulem, P, Stefansson, H, Holm, H, Gudbjartsson, D, Thorleifsson, G, Jonsdottir, I, Pedersen, OBV, Jemec, GBE & Stefansson, K 2025, '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', Journal of the American Academy of Dermatology, vol. 92, no. 4, pp. 761-772. https://doi.org/10.1016/j.jaad.2024.11.050

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title = "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 = "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 = "Amyloid Precursor Protein Secretases/genetics, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Hidradenitis Suppurativa/genetics, Humans, Male, Membrane Glycoproteins, Polymorphism, Single Nucleotide, Receptors, Notch/genetics, Wnt Proteins/genetics, Wnt Signaling Pathway/genetics, GWAS, NOTCH, inheritance, hidradenitis suppurativa, pathway analysis, causality, Wnt signaling, genetics, Notch signaling, genome-wide association study, WNT, γ-secretase",

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

note = "Copyright {\textcopyright} 2024. Published by Elsevier Inc.",

year = "2025",

month = apr,

doi = "10.1016/j.jaad.2024.11.050",

language = "English",

volume = "92",

pages = "761--772",

journal = "Journal of the American Academy of Dermatology",

issn = "0190-9622",

publisher = "Elsevier Inc.",

number = "4",

}

TY - JOUR

T1 - 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

AU - Andersen, R Kjærsgaard

AU - Stefansdottir, L

AU - Riis, P Theut

AU - Halldorsson, Gh

AU - Ferkingstad, E

AU - Oddsson, A

AU - Walters, G B

AU - Olafsdottir, Thorunn A

AU - Rutsdottir, G

AU - Zachariae, C

AU - Thomsen, S F

AU - Brodersen, T

AU - Dinh, K M

AU - Knowlton, K U

AU - Knight, S

AU - Nadauld, L D

AU - Banasik, K

AU - Brunak, S

AU - Hansen, T F

AU - Hjalgrim, H

AU - Sørensen, E

AU - Mikkelsen, C

AU - Ullum, H

AU - Nyegaard, M

AU - Bruun, M T

AU - Erikstrup, C

AU - Ostrowski, S R

AU - Eidsmo, L

AU - Saunte, D M L

AU - Sigurgeirsson, B

AU - Orvar, K B

AU - Saemundsdottir, J

AU - Melsted, P

AU - Norddahl, G L

AU - Sulem, P

AU - Stefansson, H

AU - Holm, H

AU - Gudbjartsson, D

AU - Thorleifsson, G

AU - Jonsdottir, I

AU - Pedersen, O B V

AU - Jemec, G B E

AU - Stefansson, K

PY - 2025/4

Y1 - 2025/4

N2 - 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.

AB - 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.

KW - Amyloid Precursor Protein Secretases/genetics

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Hidradenitis Suppurativa/genetics

KW - Humans

KW - Male

KW - Membrane Glycoproteins

KW - Polymorphism, Single Nucleotide

KW - Receptors, Notch/genetics

KW - Wnt Proteins/genetics

KW - Wnt Signaling Pathway/genetics

KW - GWAS

KW - NOTCH

KW - inheritance

KW - hidradenitis suppurativa

KW - pathway analysis

KW - causality

KW - Wnt signaling

KW - genetics

KW - Notch signaling

KW - genome-wide association study

KW - WNT

KW - γ-secretase

UR - https://www.scopus.com/pages/publications/85213974974

U2 - 10.1016/j.jaad.2024.11.050

DO - 10.1016/j.jaad.2024.11.050

M3 - Journal article

C2 - 39645042

SN - 0190-9622

VL - 92

SP - 761

EP - 772

JO - Journal of the American Academy of Dermatology

JF - Journal of the American Academy of Dermatology

IS - 4

ER -

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

Keywords

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