Whole-genome sequencing reveals rare and structural variants contributing to psoriasis and identifies CERCAM as a risk gene

Psoriasis vulgaris (PsV) is an immune-mediated inflammatory skin disorder with complex genetic architecture. Most genome-wide association studies (GWASs) of PsV have been limited to analyzing common single-nucleotide variants in Europeans, lacking diversity in the variant spectrum and ancestral background. To investigate the contribution of rare variants (RVs) and structural variants (SVs), we perform a whole-genome sequencing study involving 1,415 PsV cases and 3,968 controls in Japanese. A GWAS signal at IFNLR1 is fine-mapped to a 3.3-kb deletion SV disrupting an epithelium-specific putative enhancer, which is validated by PacBio long-read sequencing. Gene-based RV analyses identify two susceptibility genes: IFIH1 (p = 9.8 × 10<sup>-6</sup>) and CERCAM (p = 4.1 × 10<sup>-7</sup>). Notably, IL36RN, a causative gene for generalized pustular psoriasis, a rare and lethal multi-systemic inflammatory disorder, is associated with common PsV (p = 1.2 × 10<sup>-4</sup>). Finally, Cercam knockout (Cercam<sup>-/-</sup>) in an imiquimod-induced psoriasis mouse model aggravates dermatitis with elevated T cell retention in the subepidermis. Our study elucidates the overlooked genetic basis of PsV.

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Publication Details

Journal
Cell Genomics
Published
2025-08-22
DOI
https://doi.org/10.1016/j.xgen.2025.100978
Citations
1
Primary Topic
Psoriasis: Treatment and Pathogenesis
Type
article
Field-Weighted Citation Impact
0.80

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article

Whole-genome sequencing reveals rare and structural variants contributing to psoriasis and identifies CERCAM as a risk gene

Satoshi Fukushima, Manabu Fujimoto, Toshihiro Kishikawa, Tsukasa Matsubara et al.
1 citations
Cell Genomics
Psoriasis: Treatment and Pathogenesis
0.80
article

Whole-genome sequencing reveals rare and structural variants contributing to psoriasis and identifies CERCAM as a risk gene

Satoshi Fukushima, Manabu Fujimoto, Toshihiro Kishikawa, Tsukasa Matsubara, Mariko Komuro, Yoshihide Asano, Kimiko Nakajima, Tomomitsu Hirota, Masahiro Kamata, Tatsuhiko Naito, Akihiko Asahina, Yoshiya Tanaka, Kenichi Yamamoto, Kaori Odomari, Hidehisa Saeki, Junya Watanabe, Atsushi Kumanogoh, Mayumi Tamari, Toshimasa Yamauchi, Yuumi Nakamura, Mio Edamoto, Noah Sasa, Noriko Arase, Nobuhiro Shojima, Emi Nishida, Yukinori Okada, Shinichi Namba, Takashi Kadowaki, Fumihiko Matsuda, Junichi Furuta, Emiko Noguchi, Tatsuyoshi Kawamura, Rei Watanabe, Rika Nishikawa, Ryuya Edahiro, Hiroyuki Matsue, Mami Momose, Ippei Miyagawa, Ken Suzuki, Yosuke Ishitsuka, Saori Sakaue, Chikako Nishigori, Koichi Matsuda, Shigetoshi Sano, Koichiro Higasa, Kayo Kunimoto, Shinichi Imafuku, Masatoshi Jinnin, Akimichi Morita, Yosuke Ogawa, Hideaki Miyachi, Yuya Shirai, Hironobu Ihn, Kyuto Sonehara, Ikko Kajihara, Tetsuya Ikeda, Takashi Okamoto, Shinichi Sato, Hiroshi Nagai, Yuichi Mitsui, Takashi Satoh, Ikuma Nakagawa, Yayoi Tada, Shinji Shimada, Hiroaki Tanaka, Ichiro Katayama, Atsuko Adachi, Tatsuya Horikawa, Toshinori Bito, Masanobu Ueno, Yutaka Matsumura
article en
1 citations

Abstract

Psoriasis vulgaris (PsV) is an immune-mediated inflammatory skin disorder with complex genetic architecture. Most genome-wide association studies (GWASs) of PsV have been limited to analyzing common single-nucleotide variants in Europeans, lacking diversity in the variant spectrum and ancestral background. To investigate the contribution of rare variants (RVs) and structural variants (SVs), we perform a whole-genome sequencing study involving 1,415 PsV cases and 3,968 controls in Japanese. A GWAS signal at IFNLR1 is fine-mapped to a 3.3-kb deletion SV disrupting an epithelium-specific putative enhancer, which is validated by PacBio long-read sequencing. Gene-based RV analyses identify two susceptibility genes: IFIH1 (p = 9.8 × 10<sup>-6</sup>) and CERCAM (p = 4.1 × 10<sup>-7</sup>). Notably, IL36RN, a causative gene for generalized pustular psoriasis, a rare and lethal multi-systemic inflammatory disorder, is associated with common PsV (p = 1.2 × 10<sup>-4</sup>). Finally, Cercam knockout (Cercam<sup>-/-</sup>) in an imiquimod-induced psoriasis mouse model aggravates dermatitis with elevated T cell retention in the subepidermis. Our study elucidates the overlooked genetic basis of PsV.

Cell GenomicsVol. 5(10)
Osaka Gakuin University (JP), Jikei University School of Medicine (JP), Tokyo Medical and Dental University (JP), Brigham and Women's Hospital (US), University of Tsukuba (JP), Chiba University (JP), University of Occupational and Environmental Health Japan (JP), Wakayama Medical University (JP), Tohoku University (JP), Kyoto University (JP), Fukuoka University (JP), Nagoya City University (JP), Kobe Medical Center (JP), University of Tokyo Hospital (JP), Institute for Rheumatic Diseases (Japan) (JP), Matsubara Mayflower Hospital (JP), Kobe City Medical Center West Hospital (JP), RIKEN Center for Integrative Medical Sciences (JP), Center for Genomic Science (IT), Kagawa Prefectural Central Hospital (JP), Osaka University Hospital (JP), Toranomon Hospital (JP), Kobe University (JP), University of Yamanashi (JP), The University of Tokyo (JP), Kōchi University (JP), Nippon Medical School (JP), Teikyo University (JP), Kumamoto University (JP), The University of Osaka (JP)
Ono Pharmaceutical, Japan Society for the Promotion of Science, RIKEN, Moonshot Research and Development Program
Zero hunger
Openalex Percentile: Top 24%
Psoriasis: Treatment and Pathogenesis
0.80
DOIOpen Access PDFOpenAlex
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