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

Kyuto Sonehara¹, Rei Watanabe², Yutaka Matsumura³, Yuichi Mitsui⁴, Yosuke Ogawa⁵, Kaori Odomari⁶, Saori Sakaue⁷, Shinichi Namba⁸, Mariko Komuro⁴, Mio Edamoto⁴, Junya Watanabe⁴, Tomomitsu Hirota⁹, Noriko Arase¹⁰, Yuumi Nakamura¹¹, Kimiko Nakajima¹², Takashi Okamoto¹³, Rika Nishikawa¹⁴, Kenichi Yamamoto¹⁵, Ken Suzuki¹⁶, Toshihiro Kishikawa¹⁷, Ryuya Edahiro¹⁸, Yuya Shirai¹⁹, Tatsuhiko Naito²⁰, Noah Sasa²¹, Yosuke Ishitsuka²², Junichi Furuta²³, Kayo Kunimoto²⁴, Ikko Kajihara²⁵, Satoshi Fukushima²⁵, Hideaki Miyachi²⁶, Hiroyuki Matsue²⁶, Masahiro Kamata²⁷, Mami Momose²⁸, Ippei Miyagawa²⁹, Hiroaki Tanaka²⁹, Masanobu Ueno²⁹, Toshinori Bito¹⁴, Hiroshi Nagai¹⁴, Tetsuya Ikeda³⁰, Tatsuya Horikawa³¹, Atsuko Adachi³², Tsukasa Matsubara³³, Emi Nishida³⁴; Biobank Japan Project; Koichi Matsuda³⁵, Nobuhiro Shojima³⁶, Ikuma Nakagawa³⁷, Yoshihide Asano³⁸, Shinichi Sato³⁹, Shinichi Imafuku⁴⁰, Yayoi Tada²⁷, Chikako Nishigori¹⁴, Masatoshi Jinnin²⁴, Hironobu Ihn²⁵, Akihiko Asahina²⁸, Hidehisa Saeki⁴¹, Toshimasa Yamauchi³⁶, Takashi Kadowaki⁴², Tatsuyoshi Kawamura¹³, Shinji Shimada¹³, Ichiro Katayama⁴³, Koichiro Higasa⁴⁴, Emiko Noguchi⁴⁵, Shigetoshi Sano¹², Yoshiya Tanaka²⁹, Fumihiko Matsuda⁴⁶, Atsushi Kumanogoh⁴⁷, Mayumi Tamari⁹, Takashi Satoh⁴, Manabu Fujimoto³, Akimichi Morita³⁴, Yukinori Okada⁴⁸

Affiliations

¹ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address: qsonehara@m.u-tokyo.ac.jp.
² Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Integrative Medicine for Allergic and Immunological Diseases, Osaka University Graduate School of Medicine, Suita, Japan; Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
³ Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
⁴ Department of Immunology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
⁵ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
⁷ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Divisions of Genetics and Rheumatology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹ Division of Molecular Genetics, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan.
¹⁰ Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
¹¹ Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan; Cutaneous Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
¹² Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan.
¹³ Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
¹⁴ Division of Dermatology, Department of Internal Related, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
¹⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; Division of Health Science, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
¹⁷ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan; Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
¹⁸ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁹ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
²⁰ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²¹ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
²² Department of Integrative Medicine for Allergic and Immunological Diseases, Osaka University Graduate School of Medicine, Suita, Japan; Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
²³ Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
²⁴ Department of Dermatology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
²⁵ Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan.
²⁶ Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan.
²⁷ Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.
²⁸ Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.
²⁹ The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
³⁰ Department of Dermatology, Kobe City Hospital Organization Kobe Medical Center West Hospital, Kobe, Japan.
³¹ Department of Dermatology, Nishikobe Medical Center, Kobe, Japan.
³² Department of Dermatology, Hyogo Prefectural Kakogawa Medical Center, Kakogawa, Japan.
³³ Matsubara Mayflower Hospital, Kato, Japan.
³⁴ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
³⁵ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
³⁶ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
³⁷ Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.
³⁸ Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
³⁹ Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
⁴⁰ Department of Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
⁴¹ Department of Dermatology, Nippon Medical School, Tokyo, Japan.
⁴² Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Toranomon Hospital, Tokyo, Japan.
⁴³ Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Pigmentation Research and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
⁴⁴ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Hirakata, Japan.
⁴⁵ Department of Medical Genetics, University of Tsukuba, Tsukuba, Japan.
⁴⁶ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴⁷ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan; Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
⁴⁸ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Japan. Electronic address: yuki-okada@m.u-tokyo.ac.jp.

PMID: 40848718
DOI: 10.1016/j.xgen.2025.100978

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

Kyuto Sonehara et al. Cell Genom. 2025.

. 2025 Aug 19:100978.

doi: 10.1016/j.xgen.2025.100978. Online ahead of print.

Authors

Affiliations

¹ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. Electronic address: qsonehara@m.u-tokyo.ac.jp.
² Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Integrative Medicine for Allergic and Immunological Diseases, Osaka University Graduate School of Medicine, Suita, Japan; Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
³ Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
⁴ Department of Immunology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
⁵ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
⁷ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Divisions of Genetics and Rheumatology, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁹ Division of Molecular Genetics, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan.
¹⁰ Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan.
¹¹ Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan; Cutaneous Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
¹² Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan.
¹³ Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
¹⁴ Division of Dermatology, Department of Internal Related, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
¹⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan; Division of Health Science, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
¹⁷ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan; Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
¹⁸ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁹ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
²⁰ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²¹ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
²² Department of Integrative Medicine for Allergic and Immunological Diseases, Osaka University Graduate School of Medicine, Suita, Japan; Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
²³ Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
²⁴ Department of Dermatology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
²⁵ Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan.
²⁶ Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan.
²⁷ Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.
²⁸ Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.
²⁹ The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
³⁰ Department of Dermatology, Kobe City Hospital Organization Kobe Medical Center West Hospital, Kobe, Japan.
³¹ Department of Dermatology, Nishikobe Medical Center, Kobe, Japan.
³² Department of Dermatology, Hyogo Prefectural Kakogawa Medical Center, Kakogawa, Japan.
³³ Matsubara Mayflower Hospital, Kato, Japan.
³⁴ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
³⁵ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
³⁶ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
³⁷ Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan.
³⁸ Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
³⁹ Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
⁴⁰ Department of Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
⁴¹ Department of Dermatology, Nippon Medical School, Tokyo, Japan.
⁴² Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Toranomon Hospital, Tokyo, Japan.
⁴³ Department of Dermatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Pigmentation Research and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
⁴⁴ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Hirakata, Japan.
⁴⁵ Department of Medical Genetics, University of Tsukuba, Tsukuba, Japan.
⁴⁶ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴⁷ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan; Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita, Japan.
⁴⁸ Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Japan. Electronic address: yuki-okada@m.u-tokyo.ac.jp.

PMID: 40848718
DOI: 10.1016/j.xgen.2025.100978

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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Declaration of interests The authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources