Eight novel susceptibility loci and putative causal variants in atopic dermatitis
| Autor: | Hiroyuki Suetsugu, Yukihide Momozawa, Masaru Koido, Akari Suzuki, Nao Otomo, Nao Tanaka, Yuta Kochi, Kouhei Tomizuka, Chikashi Terao, Yoichiro Kamatani, Shiro Ikegawa, Kazuhiko Yamamoto |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Linkage disequilibrium Immunology Genome-wide association study Single-nucleotide polymorphism Locus (genetics) Biology Linkage Disequilibrium Dermatitis Atopic 03 medical and health sciences 0302 clinical medicine Japan Humans Immunology and Allergy Genetic Predisposition to Disease 1000 Genomes Project Genetic Association Studies Adaptor Proteins Signal Transducing 030304 developmental biology Genetics 0303 health sciences Polymorphism Genetic Immunity Heritability DNA-Binding Proteins Minor allele frequency Genetic Loci Case-Control Studies Expression quantitative trait loci Female Transcriptional Elongation Factors Apoptosis Regulatory Proteins 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Journal of Allergy and Clinical Immunology. 148:1293-1306 |
| ISSN: | 0091-6749 |
| DOI: | 10.1016/j.jaci.2021.04.019 |
| Popis: | 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, andIQGAP1. 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. |
| Databáze: | OpenAIRE |
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