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European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation
European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation
Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.
2041-1723
Budu-Aggrey, Ashley
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Mitchell, Ruth
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Reis, Kadri
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Reigo, Anu
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Magi, Reedik
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Nelis, Mari
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Flatley, Christopher
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Lominchar, Jesus V.T.
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Bork-Jensen, Jette
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Marenholz, Ingo
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Arnau-Soler, Alexi
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Jeong, Ayoung
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Fawcett, Katherine A
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Baurecht, Hansjörg
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Titcombe, Philip
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Godfrey, Keith
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Barton, Sheila
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Budu-Aggrey, Ashley
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Shringarpure, Suyash S
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Mitchell, Ruth
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Reis, Kadri
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Reigo, Anu
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Magi, Reedik
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Nelis, Mari
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Brumpton, Ben M.
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Herrera-Luis, Esther
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Lominchar, Jesus V.T.
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Bork-Jensen, Jette
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Marenholz, Ingo
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Arnau-Soler, Alexi
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Jeong, Ayoung
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Fawcett, Katherine A
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Baurecht, Hansjörg
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Titcombe, Philip
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Godfrey, Keith
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Barton, Sheila
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Holloway, John
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Paternoster, Lavinia
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Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S, Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Magi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Navais, Pol-Sole, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Alexi, Jeong, Ayoung, Fawcett, Katherine A, Baurecht, Hansjörg, Titcombe, Philip, Godfrey, Keith, Barton, Sheila, Holloway, John and Paternoster, Lavinia (2023) European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation. Nature Communications, 14 (1), [6172]. (doi:10.1038/s41467-023-41180-2).

Record type: Article

Abstract

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

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Accepted/In Press date: 24 August 2023
e-pub ahead of print date: 4 October 2023
Published date: 4 October 2023
Additional Information: Funding Information: For this work, A.B.-A., S.J.B. and L.P. were funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 821511 (BIOMAP). The J.U. receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author’s view and the J.U. is not responsible for any use that may be made of the information it contains. A.B.A., M.K.S., J.L.M., and L.P. and work in a research unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4). LP received funding from the British Skin Foundation (8010 Innovative Project) and the Academy of Medical Sciences Springboard Award, which is supported by the Wellcome Trust, The Government Department for Business, Energy and Industrial Strategy, the Global Challenges Research Fund and the British Heart Foundation [SBF003\1094]. S.J.B. holds a Wellcome Trust Senior Research Fellowship in Clinical Science [220875/Z/20/Z]. S.H. is supported by a Vera Davie Study and Research Sabbatical Bursary, NRF Thuthuka Grant (117721), NRF Competitive Support for Unrated Researcher (138072), MRC South Africa under a Self-initiated grant. M.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 949906). Thanks to Sergi Sayols (developer of rrvgo), who provided additional code to alter the scatter plot produced by rrvgo to only display parent terms, and to Gibran Hemani (University of Bristol) who provided valuable guidance on the comparison of effects between ancestries. This publication is the work of the authors and LP will serve as guarantor for the contents of this paper. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol— http://www.bristol.ac.uk/acrc/ . Individual cohort acknowledgements are in the Supplementary Methods. Funding Information: For this work, A.B.-A., S.J.B. and L.P. were funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 821511 (BIOMAP). The J.U. receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author’s view and the J.U. is not responsible for any use that may be made of the information it contains. A.B.A., M.K.S., J.L.M., and L.P. and work in a research unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4). LP received funding from the British Skin Foundation (8010 Innovative Project) and the Academy of Medical Sciences Springboard Award, which is supported by the Wellcome Trust, The Government Department for Business, Energy and Industrial Strategy, the Global Challenges Research Fund and the British Heart Foundation [SBF003\1094]. S.J.B. holds a Wellcome Trust Senior Research Fellowship in Clinical Science [220875/Z/20/Z]. S.H. is supported by a Vera Davie Study and Research Sabbatical Bursary, NRF Thuthuka Grant (117721), NRF Competitive Support for Unrated Researcher (138072), MRC South Africa under a Self-initiated grant. M.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 949906). Thanks to Sergi Sayols (developer of rrvgo), who provided additional code to alter the scatter plot produced by rrvgo to only display parent terms, and to Gibran Hemani (University of Bristol) who provided valuable guidance on the comparison of effects between ancestries. This publication is the work of the authors and LP will serve as guarantor for the contents of this paper. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol—http://www.bristol.ac.uk/acrc/. Individual cohort acknowledgements are in the Supplementary Methods. Publisher Copyright: © 2023, Springer Nature Limited.

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Local EPrints ID: 483325
URI: http://eprints.soton.ac.uk/id/eprint/483325
ISSN: 2041-1723
PURE UUID: deafed87-0895-4b7d-a7b8-e7f47113aca9
ORCID for Philip Titcombe: ORCID iD orcid.org/0000-0002-7797-8571
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Sheila Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 27 Oct 2023 17:09
Last modified: 18 Mar 2024 03:27

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Contributors

Author: Ashley Budu-Aggrey
Author: Anna Kilanowski
Author: Maria K. Sobczyk
Author: Suyash S Shringarpure
Author: Ruth Mitchell
Author: Kadri Reis
Author: Anu Reigo
Author: Reedik Magi
Author: Mari Nelis
Author: Nao Tanaka
Author: Ben M. Brumpton
Author: Laurent F. Thomas
Author: Pol-Sole Navais
Author: Christopher Flatley
Author: Antonio Espuela-Ortiz
Author: Esther Herrera-Luis
Author: Jesus V.T. Lominchar
Author: Jette Bork-Jensen
Author: Ingo Marenholz
Author: Alexi Arnau-Soler
Author: Ayoung Jeong
Author: Katherine A Fawcett
Author: Hansjörg Baurecht
Author: Philip Titcombe ORCID iD
Author: Keith Godfrey ORCID iD
Author: Sheila Barton ORCID iD
Author: John Holloway ORCID iD
Author: Lavinia Paternoster

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