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. 2025 Oct 8;5(10):100978.
doi: 10.1016/j.xgen.2025.100978. Epub 2025 Aug 22.

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

Kyuto Sonehara  1 , Rei Watanabe  2 , Yutaka Matsumura  3 , Yuichi Mitsui  4 , Yosuke Ogawa  5 , Kaori Odomari  6 , Saori Sakaue  7 , Shinichi Namba  8 , Mariko Komuro  4 , Mio Edamoto  4 , Junya Watanabe  4 , Tomomitsu Hirota  9 , Noriko Arase  10 , Yuumi Nakamura  11 , Kimiko Nakajima  12 , Takashi Okamoto  13 , Rika Nishikawa  14 , Kenichi Yamamoto  15 , Ken Suzuki  16 , Toshihiro Kishikawa  17 , Ryuya Edahiro  18 , Yuya Shirai  19 , Tatsuhiko Naito  20 , Noah Sasa  21 , Yosuke Ishitsuka  22 , Junichi Furuta  23 , Kayo Kunimoto  24 , Ikko Kajihara  25 , Satoshi Fukushima  25 , Hideaki Miyachi  26 , Hiroyuki Matsue  26 , Masahiro Kamata  27 , Mami Momose  28 , Ippei Miyagawa  29 , Hiroaki Tanaka  29 , Masanobu Ueno  29 , Toshinori Bito  14 , Hiroshi Nagai  14 , Tetsuya Ikeda  30 , Tatsuya Horikawa  31 , Atsuko Adachi  32 , Tsukasa Matsubara  33 , Emi Nishida  34 ; Biobank Japan Project; Koichi Matsuda  35 , Nobuhiro Shojima  36 , Ikuma Nakagawa  37 , Yoshihide Asano  38 , Shinichi Sato  39 , Shinichi Imafuku  40 , Yayoi Tada  27 , Chikako Nishigori  14 , Masatoshi Jinnin  24 , Hironobu Ihn  25 , Akihiko Asahina  28 , Hidehisa Saeki  41 , Toshimasa Yamauchi  36 , Takashi Kadowaki  42 , Tatsuyoshi Kawamura  13 , Shinji Shimada  13 , Ichiro Katayama  43 , Koichiro Higasa  44 , Emiko Noguchi  45 , Shigetoshi Sano  12 , Yoshiya Tanaka  29 , Fumihiko Matsuda  46 , Atsushi Kumanogoh  47 , Mayumi Tamari  9 , Takashi Satoh  4 , Manabu Fujimoto  3 , Akimichi Morita  34 , Yukinori Okada  48
Affiliations
Free article

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

Kyuto Sonehara et al. Cell Genom. .
Free article

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.

Keywords: gene-based analysis; genome-wide association study; knockout mouse model; psoriasis vulgaris; rare variant; single-cell RNA-seq; spatial transcriptome analysis; structural variant; whole-genome sequencing.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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