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

Ashley Budu-Aggrey, Anna Kilanowski, Maria K. Sobczyk, Suyash S. Shringarpure, Ruth Mitchell, Kadri Reis, Anu Reigo, Reedik Mägi, Mari Nelis, Nao Tanaka, Ben M. Brumpton, Laurent F. Thomas, Pol Sole-Navais, Christopher Flatley, Antonio Espuela-Ortiz, Esther Herrera-Luis, Jesus V.T. Lominchar, Jette Bork-Jensen, Ingo Marenholz, Aleix Arnau-SolerAyoung Jeong, Katherine A. Fawcett, Hansjorg Baurecht, Elke Rodriguez, Alexessander Couto Alves, Ashish Kumar, Patrick M. Sleiman, Xiao Chang, Carolina Medina-Gomez, Chen Hu, Cheng jian Xu, Cancan Qi, Sarah El-Heis, Philip Titcombe, Elie Antoun, João Fadista, Carol A. Wang, Elisabeth Thiering, Baojun Wu, Sara Kress, Dilini M. Kothalawala, Latha Kadalayil, Jiasong Duan, Hongmei Zhang, Sabelo Hadebe, Thomas Hoffmann, Eric Jorgenson, Hélène Choquet, Neil Risch, Pål Njølstad, Ole A. Andreassen, Stefan Johansson, Catarina Almqvist, Tong Gong, Vilhelmina Ullemar, Robert Karlsson, Patrik K.E. Magnusson, Agnieszka Szwajda, Esteban G. Burchard, Jacob P. Thyssen, Torben Hansen, Line L. Kårhus, Thomas M. Dantoft, Alexander C.S.N. Jeanrenaud, Ahla Ghauri, Andreas Arnold, Georg Homuth, Susanne Lau, Markus M. Nöthen, Norbert Hübner, Medea Imboden, Alessia Visconti, Mario Falchi, Veronique Bataille, Pirro Hysi, Natalia Ballardini, Dorret I. Boomsma, Jouke J. Hottenga, Martina Müller-Nurasyid, Tarunveer S. Ahluwalia, Jakob Stokholm, Bo Chawes, Ann Marie M. Schoos, Ana Esplugues, Mariona Bustamante, Benjamin Raby, Syed Arshad, Chris German, Tõnu Esko, Lili A. Milani, Andres Metspalu, Chikashi Terao, Katrina Abuabara, Mari Løset, Kristian Hveem, Bo Jacobsson, Maria Pino-Yanes, David P. Strachan, Niels Grarup, Allan Linneberg, Young Ae Lee, Nicole Probst-Hensch, Stephan Weidinger, Marjo Riitta Jarvelin, Erik Melén, Hakon Hakonarson, Alan D. Irvine, Deborah Jarvis, Tamar Nijsten, Liesbeth Duijts, Judith M. Vonk, Gerard H. Koppelmann, Keith M. Godfrey, Sheila J. Barton, Bjarke Feenstra, Craig E. Pennell, Peter D. Sly, Patrick G. Holt, L. Keoki Williams, Hans Bisgaard, Klaus Bønnelykke, John Curtin, Angela Simpson, Clare Murray, Tamara Schikowski, Supinda Bunyavanich, Scott T. Weiss, John W. Holloway, Josine L. Min, Sara J. Brown, Marie Standl, Lavinia Paternoster*

*Corresponding author for this work

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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.

Original languageEnglish
Article number6172
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 4 Oct 2023

Bibliographical note

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.



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