Genome-wide meta-analysis implicates variation affecting mast cell biology in urticaria

Urticaria is characterized by inappropriate mast cell degranulation that leads to the development of wheals and/or angioedema. Twin and family studies indicate that there is a substantial heritable component to urticaria risk. To identify genomic loci at which common genetic variation influence urticaria susceptibility. Genome-wide association studies (GWAS) of urticaria (including all subtypes) from three European cohorts (UK Biobank, FinnGen, and the HUNT Study) were combined through statistical meta-analysis (14,306 urticaria cases and 650,664 controls). Cases were identified from electronic healthcare 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. Genome-wide significant associations (p < 5 x 10-8) were identified at six independent loci. These included two 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 other four 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 (PPcoloc) = 0.89) and FCER1A (PPcoloc = 0.91) in skin. Common genetic variation influencing the risk of developing urticaria was identified at six genomic loci. The relationship of genes with roles in mast cell biology with several association signals implicates genetic variability of specific components of mast cell function in the development of urticaria.