Eight novel susceptibility loci and putative causal variants in atopic dermatitis

Nao Tanaka; Masaru Koido; Akari Suzuki; Nao Otomo; Hiroyuki Suetsugu; Yuta Kochi; Kouhei Tomizuka; Yukihide Momozawa; Yoichiro Kamatani; Biobank Japan Project; Shiro Ikegawa; Kazuhiko Yamamoto; Chikashi Terao

doi:10.1016/j.jaci.2021.04.019

Eight novel susceptibility loci and putative causal variants in atopic dermatitis

J Allergy Clin Immunol. 2021 Nov;148(5):1293-1306. doi: 10.1016/j.jaci.2021.04.019. Epub 2021 Jun 8.

Authors

Affiliations

¹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
² Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
³ Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Tokyo, Japan; Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
⁵ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Tokyo, Japan; Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁶ Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
⁷ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁸ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁰ Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹¹ Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Tokyo, Japan.
¹² Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan; Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address: chikashi.terao@riken.jp.

PMID: 34116867
DOI: 10.1016/j.jaci.2021.04.019

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 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.

Keywords: Atopic dermatitis; gene expression; genetic study; immune cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Apoptosis Regulatory Proteins / genetics*
Case-Control Studies
DNA-Binding Proteins / genetics
Dermatitis, Atopic / genetics*
Female
Genetic Association Studies
Genetic Loci / genetics*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Immunity / genetics
Japan / epidemiology
Linkage Disequilibrium
Male
Polymorphism, Genetic
Transcriptional Elongation Factors / genetics

Substances

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
DNA-Binding Proteins
NLRP10 protein, human
Transcriptional Elongation Factors
AFF1 protein, human