TY - JOUR
T1 - Genome-wide meta-analysis implicates variation affecting mast cell biology in urticaria
AU - McSweeney, Sheila Mary
AU - Saklatvala, Jake
AU - Rispoli, Rossella
AU - Ganier, Clarisse
AU - Woszczek, Grzegorz
AU - Thomas, Laurent
AU - Hveem, Kristian
AU - Løset, Mari
AU - Dand, Nick
AU - Tziotzios, Christos
AU - Simpson, Michael
AU - McGrath, John Alexander
N1 - Funding Information:
Supported by a Medical Research Council Clinical Research Training Fellowship (MR/V006746/1 [to S.M.M.]) and grants from the Liaison Committee for Education, Research, and Innovation in Central Norway (to M.L.). The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology.
Funding Information:
Supported by a Medical Research Council Clinical Research Training Fellowship (MR/V006746/1 [to S.M.M.]) and grants from the Liaison Committee for Education, Research, and Innovation in Central Norway (to M.L.). The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology.Disclosure of potential conflict of interest: S. M. McSweeney is a subinvestigator on the Pfizer-funded ALLEGRO clinical trial in alopecia areata. C. Tziotzios is a principal and (national) chief investigator on the Pfizer-funded ALLEGRO clinical trial in alopecia areata; in addition, he provides consulting services to Pfizer and has received speaker fees from Leo Pharma. The rest of the authors declare that they have no relevant conflicts of interest.
Funding Information:
This research has been conducted using the UK Biobank Resource under application no. 15147. It uses data provided by patients and collected by the National Health Service (NHS) as part of their care and support. Copyright 2023, NHS England. Reused with the permission of NHS England and UK Biobank. All rights reserved. HUNT is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU–Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St. Olav's Hospital and the Faculty of Medicine and Health Sciences, NTNU.
Publisher Copyright:
© 2023 The Authors
PY - 2024/2
Y1 - 2024/2
N2 - Background: Urticaria is characterized by inappropriate mast cell degranulation leading to the development of wheals and/or angioedema. Twin and family studies indicate that there is a substantial heritable component to urticaria risk. Objective: Our aim was to identify genomic loci at which common genetic variation influences urticaria susceptibility. Methods: Genome-wide association studies of urticaria (including all subtypes) from 3 European cohorts (UK Biobank, FinnGen, and the Trøndelag Health Study [HUNT]) were combined through statistical meta-analysis (14,306 urticaria cases and 650,664 controls). Cases were identified via electronic health care records from primary and/or secondary care. To identify putative causal variants and genes, statistical fine-mapping, colocalization, and interrogation of publicly available single-cell transcriptome sequencing resources were performed. Results: Genome-wide significant associations (P < 5 × 10–8) were identified at 6 independent loci. These included 2 previously reported association signals at 1q44 and the human leucocyte antigen region on chromosome 6. Genes with expected or established roles in mast cell biology were associated with the 4 other genome-wide association signals (GCSAML, FCER1A, TPSAB1, and CBLB). Colocalization of association signals consistent with the presence of shared causal variants was observed between urticaria susceptibility and increased expression of GCSAML (posterior probability of colocalization [PPcoloc] = 0.89) and FCER1A (PPcoloc = 0.91) in skin. Conclusion: Common genetic variation influencing the risk of developing urticaria was identified at 6 genomic loci. The relationship between genes with roles in mast cell biology and several association signals implicates genetic variability of specific components of mast cell function in the development of urticaria.
AB - Background: Urticaria is characterized by inappropriate mast cell degranulation leading to the development of wheals and/or angioedema. Twin and family studies indicate that there is a substantial heritable component to urticaria risk. Objective: Our aim was to identify genomic loci at which common genetic variation influences urticaria susceptibility. Methods: Genome-wide association studies of urticaria (including all subtypes) from 3 European cohorts (UK Biobank, FinnGen, and the Trøndelag Health Study [HUNT]) were combined through statistical meta-analysis (14,306 urticaria cases and 650,664 controls). Cases were identified via electronic health care records from primary and/or secondary care. To identify putative causal variants and genes, statistical fine-mapping, colocalization, and interrogation of publicly available single-cell transcriptome sequencing resources were performed. Results: Genome-wide significant associations (P < 5 × 10–8) were identified at 6 independent loci. These included 2 previously reported association signals at 1q44 and the human leucocyte antigen region on chromosome 6. Genes with expected or established roles in mast cell biology were associated with the 4 other genome-wide association signals (GCSAML, FCER1A, TPSAB1, and CBLB). Colocalization of association signals consistent with the presence of shared causal variants was observed between urticaria susceptibility and increased expression of GCSAML (posterior probability of colocalization [PPcoloc] = 0.89) and FCER1A (PPcoloc = 0.91) in skin. Conclusion: Common genetic variation influencing the risk of developing urticaria was identified at 6 genomic loci. The relationship between genes with roles in mast cell biology and several association signals implicates genetic variability of specific components of mast cell function in the development of urticaria.
KW - genome-wide association study
KW - mast cells
KW - meta-analysis
KW - Urticaria
UR - http://www.scopus.com/inward/record.url?scp=85173218395&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2023.08.033
DO - 10.1016/j.jaci.2023.08.033
M3 - Article
C2 - 37690594
AN - SCOPUS:85173218395
SN - 0091-6749
VL - 153
SP - 521-526.e11
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -