| Title: | Whole-genome sequencing reveals rare and structural variants contributing to psoriasis and identifies CERCAM as a risk gene |
| Journal: | Cell Genomics |
| Published: | 22 Aug 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40848718/ |
| DOI: | https://doi.org/10.1016/j.xgen.2025.100978 |
| URL: | https://www.cell.com/cell-genomics/pdf/S2666-979X(25)00234-4.pdf |
Publication 19685
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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 × 10-6) and CERCAM (p = 4.1 × 10-7). 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 × 10-4). Finally, Cercam knockout (Cercam-/-) 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.</p>
13 Keywords
- Animals
- Disease Models, Animal
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Interferon-Induced Helicase, IFIH1
- Male
- Mice
- Mice, Knockout
- Polymorphism, Single Nucleotide
- Psoriasis
- Whole Genome Sequencing
72 Authors
- Kyuto Sonehara
- Rei Watanabe
- Yutaka Matsumura
- Yuichi Mitsui
- Yosuke Ogawa
- Kaori Odomari
- Saori Sakaue
- Shinichi Namba
- Mariko Komuro
- Mio Edamoto
- Junya Watanabe
- Tomomitsu Hirota
- Noriko Arase
- Yuumi Nakamura
- Kimiko Nakajima
- Takashi Okamoto
- Rika Nishikawa
- Kenichi Yamamoto
- Ken Suzuki
- Toshihiro Kishikawa
- Ryuya Edahiro
- Yuya Shirai
- Tatsuhiko Naito
- Noah Sasa
- Yosuke Ishitsuka
- Junichi Furuta
- Kayo Kunimoto
- Ikko Kajihara
- Satoshi Fukushima
- Hideaki Miyachi
- Hiroyuki Matsue
- Masahiro Kamata
- Mami Momose
- Ippei Miyagawa
- Hiroaki Tanaka
- Masanobu Ueno
- Toshinori Bito
- Hiroshi Nagai
- Tetsuya Ikeda
- Tatsuya Horikawa
- Atsuko Adachi
- Tsukasa Matsubara
- Emi Nishida
- Biobank Japan Project
- Koichi Matsuda
- Nobuhiro Shojima
- Ikuma Nakagawa
- Yoshihide Asano
- Shinichi Sato
- Shinichi Imafuku
- Yayoi Tada
- Chikako Nishigori
- Masatoshi Jinnin
- Hironobu Ihn
- Akihiko Asahina
- Hidehisa Saeki
- Toshimasa Yamauchi
- Takashi Kadowaki
- Tatsuyoshi Kawamura
- Shinji Shimada
- Ichiro Katayama
- Koichiro Higasa
- Emiko Noguchi
- Shigetoshi Sano
- Yoshiya Tanaka
- Fumihiko Matsuda
- Atsushi Kumanogoh
- Mayumi Tamari
- Takashi Satoh
- Manabu Fujimoto
- Akimichi Morita
- Yukinori Okada
1 Application
| Application ID | Title |
|---|---|
| 47821 | Trans-ethnic GWAS meta-analysis and exploration of trait-relevant genetic architecture. |
Enabling scientific discoveries that improve human health