GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region

Yuki Ishikawa; Nao Tanaka; Yoshihide Asano; Masanari Kodera; Yuichiro Shirai; Mitsuteru Akahoshi; Minoru Hasegawa; Takashi Matsushita; Kazuyoshi Saito; Sei-Ichiro Motegi; Hajime Yoshifuji; Ayumi Yoshizaki; Tomohiro Kohmoto; Kae Takagi; Akira Oka; Miho Kanda; Yoshihito Tanaka; Yumi Ito; Kazuhisa Nakano; Hiroshi Kasamatsu; Akira Utsunomiya; Akiko Sekiguchi; Hiroaki Niiro; Masatoshi Jinnin; Katsunari Makino; Takamitsu Makino; Hironobu Ihn; Motohisa Yamamoto; Chisako Suzuki; Hiroki Takahashi; Emi Nishida; Akimichi Morita; Toshiyuki Yamamoto; Manabu Fujimoto; Yuya Kondo; Daisuke Goto; Takayuki Sumida; Naho Ayuzawa; Hidetoshi Yanagida; Tetsuya Horita; Tatsuya Atsumi; Hirahito Endo; Yoshihito Shima; Atsushi Kumanogoh; Jun Hirata; Nao Otomo; Hiroyuki Suetsugu; Yoshinao Koike; Kohei Tomizuka; Soichiro Yoshino; Xiaoxi Liu; Shuji Ito; Keiko Hikino; Akari Suzuki; Yukihide Momozawa; Shiro Ikegawa; Yoshiya Tanaka; Osamu Ishikawa; Kazuhiko Takehara; Takeshi Torii; Shinichi Sato; Yukinori Okada; Tsuneyo Mimori; Fumihiko Matsuda; Koichi Matsuda; Tiffany Amariuta; Issei Imoto; Keitaro Matsuo; Masataka Kuwana; Yasushi Kawaguchi; Koichiro Ohmura; Chikashi Terao

doi:10.1038/s41467-023-44541-z

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region

Nat Commun. 2024 Jan 31;15(1):319. doi: 10.1038/s41467-023-44541-z.

Authors

Yuki Ishikawa¹, Nao Tanaka^{1

2}, Yoshihide Asano^{3

4}, Masanari Kodera⁵, Yuichiro Shirai⁶, Mitsuteru Akahoshi^{7

8}, Minoru Hasegawa⁹, Takashi Matsushita¹⁰, Kazuyoshi Saito¹¹, Sei-Ichiro Motegi¹², Hajime Yoshifuji¹³, Ayumi Yoshizaki⁴, Tomohiro Kohmoto¹⁴, Kae Takagi¹⁵, Akira Oka¹⁶, Miho Kanda⁵, Yoshihito Tanaka⁵, Yumi Ito⁵, Kazuhisa Nakano¹¹, Hiroshi Kasamatsu⁹, Akira Utsunomiya⁹, Akiko Sekiguchi¹², Hiroaki Niiro⁷, Masatoshi Jinnin¹⁷, Katsunari Makino¹⁸, Takamitsu Makino¹⁸, Hironobu Ihn¹⁸, Motohisa Yamamoto¹⁹, Chisako Suzuki²⁰, Hiroki Takahashi²⁰, Emi Nishida^{21

22}, Akimichi Morita²¹, Toshiyuki Yamamoto²³, Manabu Fujimoto²⁴, Yuya Kondo²⁵, Daisuke Goto²⁵, Takayuki Sumida²⁵, Naho Ayuzawa²⁶, Hidetoshi Yanagida²⁶, Tetsuya Horita²⁷, Tatsuya Atsumi²⁷, Hirahito Endo²⁸, Yoshihito Shima²⁹, Atsushi Kumanogoh²⁹, Jun Hirata³⁰, Nao Otomo¹, Hiroyuki Suetsugu¹, Yoshinao Koike¹, Kohei Tomizuka¹, Soichiro Yoshino¹, Xiaoxi Liu¹, Shuji Ito¹, Keiko Hikino³¹, Akari Suzuki³², Yukihide Momozawa³³, Shiro Ikegawa³⁴, Yoshiya Tanaka¹¹, Osamu Ishikawa¹², Kazuhiko Takehara¹⁰, Takeshi Torii³⁵, Shinichi Sato⁴, Yukinori Okada³⁰, Tsuneyo Mimori^{13

36}, Fumihiko Matsuda³⁷, Koichi Matsuda^{38

39}, Tiffany Amariuta^{40

41

42

43

44}, Issei Imoto⁴⁵, Keitaro Matsuo⁴⁶, Masataka Kuwana⁶, Yasushi Kawaguchi⁴⁷, Koichiro Ohmura¹³, Chikashi Terao^{48

49

50}

Affiliations

¹ RIKEN Center for Integrative Medical Sciences, The Laboratory for Statistical and Translational Genetics, Yokohama, Japan.
² Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
³ Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
⁴ Department of Dermatology, The University of Tokyo, Tokyo, Japan.
⁵ Department of Dermatology, Chukyo Hospital, Japan Community Health Care Organization, Nagoya, Japan.
⁶ Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.
⁷ Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
⁸ Department of Rheumatology, Saga University Hospital, Saga, Japan.
⁹ Faculty of Medical Sciences, Department of Dermatology, University of Fukui, Fukui, Japan.
¹⁰ Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
¹¹ The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.
¹² Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
¹³ Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁴ Aichi Cancer Center Research Institute, Division of Molecular Genetics, Nagoya, Japan.
¹⁵ Tokyo Women's Medical University, Adachi Medical Center, Tokyo, Japan.
¹⁶ Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Japan.
¹⁷ Department of Dermatology, Wakayama Medical University Graduate School of Medicine, Wakayama, Japan.
¹⁸ Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
¹⁹ Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
²⁰ Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
²¹ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
²² Department of Dermatology, Okazaki City Hospital, Okazaki, Japan.
²³ Department of Dermatology, Fukushima Medical University, School of Medicine, Fukushima, Japan.
²⁴ Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan.
²⁵ Department of Rheumatology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
²⁶ Department of Clinical Immunology, National Hospital Organization, Utano National Hospital, Kyoto, Japan.
²⁷ Faculty of Medicine and Graduate School of Medicine, Department of Rheumatology, Endocrinology and Nephrology, Hokkaido University, Sapporo, Japan.
²⁸ Omori Medical Center, Toho University, Rheumatic Disease Center, Tokyo, Japan.
²⁹ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
³⁰ Immunology Frontier Center, Osaka University, Statistical Immunology, Osaka, Japan.
³¹ RIKEN Center for Integrative Medical Sciences, The Laboratory for Pharmacogenomics, Yokohama, Japan.
³² RIKEN Center for Integrative Medical Sciences, The Laboratory for Autoimmune Diseases, Yokohama, Japan.
³³ RIKEN Center for Integrative Medical Sciences, The Laboratory for Genotyping Development, Yokohama, Japan.
³⁴ RIKEN Center for Integrative Medical Sciences, The Laboratory for Bone and Joint Diseases, Yokohama, Japan.
³⁵ Torii Clinic, Maizuru, Japan.
³⁶ Ijinkai Takeada General Hospital, Kyoto, Japan.
³⁷ Graduate School of Medicine, Kyoto University, Center for Genomic Medicine, Kyoto, Japan.
³⁸ Institute of Medical Science, The University of Tokyo, Laboratory of Genome Technology, Human Genome Center, Tokyo, Japan.
³⁹ Department of Computational Biology and Medical Sciences, Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁴⁰ Center for Data Sciences, Harvard Medical School, Boston, MA, USA.
⁴¹ Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴³ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁴⁴ Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA.
⁴⁵ Aichi Cancer Center Research Institute, Nagoya, Japan.
⁴⁶ Aichi Cancer Center Research Institute, Division of Cancer Epidemiology and Prevention, Nagoya, Japan.
⁴⁷ Tokyo Women's Medical University, Division of Rheumatology, Department of Internal Medicine, Tokyo, Japan.
⁴⁸ RIKEN Center for Integrative Medical Sciences, The Laboratory for Statistical and Translational Genetics, Yokohama, Japan. [email protected].
⁴⁹ Shizuoka General Hospital, The Clinical Research Center, Shizuoka, Japan. [email protected].
⁵⁰ The Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. [email protected].

Abstract

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Publication types

Meta-Analysis

MeSH terms

Genetic Loci
Genetic Predisposition to Disease* / genetics
Genetic Risk Score
Genome-Wide Association Study
Humans
Interferon Regulatory Factors / genetics
Polymorphism, Single Nucleotide
Receptors, IgG / genetics
Scleroderma, Systemic* / genetics

Substances

Receptors, IgG
Interferon Regulatory Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding