Eight novel susceptibility loci and putative causal variants in atopic dermatitis
Abstract
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 polyge…
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There are dozens of AD susceptibility loci characterized in diverse populations, which mediate functions such as response to interferon gamma (IFNγ), innate immunity, T lymphocyte functions, and epidermal barrier dysfunctions.
“There are dozens of AD susceptibility loci characterized in diverse populations, which mediate functions such as response to interferon gamma (IFNγ), innate immunity, T lymphocyte functions, and epidermal barrier dysfunctions (Table 1).”
From Update on the pathogenesis of atopic dermatitis. (2024) · cites this paper as [29]
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- Authors
- Tanaka, N., Koido, M., Suzuki, A., Otomo, N., Suetsugu, H., Kochi, Y., Tomizuka, K., Momozawa, Y., Kamatani, Y., Ikegawa, S., Yamamoto, K., & Terao, C.
- Affiliations
- Tokyo Medical and Dental University (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Keio University (JP)
- Kyushu University (JP)
- RIKEN (JP)
- Shizuoka University (JP)
- Corresponding author
- Terao, Chikashi
- ORCID
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 148
- Issue
- 5
- Pages
- 1293-1306
- ISSN
- 0091-6749 (ISSN-L)
- OpenAlex
- W3166504948
- Cited by
- 74
- References
- 6
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 22 · 2023: 14 · 2022: 14 · 2021: 2
- FWCI
- 11.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Agency for Medical Research and Development
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- atopic dermatitis, genetic susceptibility loci, causal variants, Japanese population, NLRP10, CCDC80, SMAD4, CD4+ T cells, polygenic architecture, heritability, skin cells, immune pathways, ZBTB38, TRAF3, IQGAP1, EHMT1, EGR2, ITGB8
- MeSH terms
- Dermatitis, Atopic, DNA-Binding Proteins, Female, Humans, Immunity, Japan, Male, Polymorphism, Genetic, Linkage Disequilibrium, Case-Control Studies, Genetic Predisposition to Disease, Transcriptional Elongation Factors, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Genome-Wide Association Study, Genetic Loci, Genetic Association Studies
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