Eight novel susceptibility loci and putative causal variants in atopic dermatitis

Background: Atopic dermatitis (AD) is the most common allergic disease in the world. While genetic components play critical roles in its pathophysiology, a large proportion of its genetic background is still unexplored. Objectives: This study sought to illuminate the genetic associations with AD using genome-wide association study (GWAS) and its downstream analyses. Methods: This study conducted a GWAS for AD comprising 2,639 cases and 115,648 controls in the Japanese population, followed by a trans-ethnic meta-analysis with UK Biobank data and downstream analyses including partitioning heritability analysis by linkage disequilibrium score regression. Results: This study identified 17 significant susceptibility loci, among which 4 loci-AFF1, ITGB8, EHMT1, and EGR2-were novel in the Japanese GWAS. The trans-ethnic meta-analysis revealed 4 additional novel loci, namely-ZBTB38, LOC105755953/LOC101928272, TRAF3, and IQGAP1. This study found a missense variant (R243W) with a deleterious functional effect in NLRP10 and a variant altering expression of CCDC80 via enhancer expression as highly likely causal variants. These 2 regions were Asian-specific, and these population-specific associations could be explained by the frequency of causal variants. The gene-based test showed SMAD4 as an additional novel significant locus. Downstream analyses revealed substantial overlap of GWAS significant signals in enhancers of skin cells and immune cells, especially CD4 T cells. A highly shared polygenic architecture of AD between Europeans and Asians was also found. Conclusions: This study identified Japanese-specific loci and novel significant loci shared by different populations. Two putative causal variants were illuminated in Japanese-specific loci. Trans ethnic analyses revealed strong heritability enrichment in immune related pathways, and relevant cell types shared among populations. (J Allergy Clin Immunol 2021;148:1293-306.)