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 and Chikashi Terao ()
Additional contact information
Yuki Ishikawa: The Laboratory for Statistical and Translational Genetics
Nao Tanaka: The Laboratory for Statistical and Translational Genetics
Yoshihide Asano: Tohoku University Graduate School of Medicine
Masanari Kodera: Chukyo Hospital, Japan Community Health Care Organization
Yuichiro Shirai: Nippon Medical School Graduate School of Medicine
Mitsuteru Akahoshi: Kyushu University Graduate School of Medical Sciences
Minoru Hasegawa: University of Fukui
Takashi Matsushita: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
Kazuyoshi Saito: University of Occupational and Environmental Health, Japan
Sei-ichiro Motegi: Gunma University Graduate School of Medicine
Hajime Yoshifuji: Graduate School of Medicine, Kyoto University
Ayumi Yoshizaki: The University of Tokyo
Tomohiro Kohmoto: Division of Molecular Genetics
Kae Takagi: Tokyo Women’s Medical University, Adachi Medical Center
Akira Oka: Tokai University School of Medicine
Miho Kanda: Chukyo Hospital, Japan Community Health Care Organization
Yoshihito Tanaka: Chukyo Hospital, Japan Community Health Care Organization
Yumi Ito: Chukyo Hospital, Japan Community Health Care Organization
Kazuhisa Nakano: University of Occupational and Environmental Health, Japan
Hiroshi Kasamatsu: University of Fukui
Akira Utsunomiya: University of Fukui
Akiko Sekiguchi: Gunma University Graduate School of Medicine
Hiroaki Niiro: Kyushu University Graduate School of Medical Sciences
Masatoshi Jinnin: Wakayama Medical University Graduate School of Medicine
Katsunari Makino: Faculty of Life Sciences, Kumamoto University
Takamitsu Makino: Faculty of Life Sciences, Kumamoto University
Hironobu Ihn: Faculty of Life Sciences, Kumamoto University
Motohisa Yamamoto: The University of Tokyo
Chisako Suzuki: Sapporo Medical University School of Medicine
Hiroki Takahashi: Sapporo Medical University School of Medicine
Emi Nishida: Nagoya City University Graduate School of Medical Sciences
Akimichi Morita: Nagoya City University Graduate School of Medical Sciences
Toshiyuki Yamamoto: Fukushima Medical University, School of Medicine
Manabu Fujimoto: Osaka University
Yuya Kondo: Institute of Medicine, University of Tsukuba
Daisuke Goto: Institute of Medicine, University of Tsukuba
Takayuki Sumida: Institute of Medicine, University of Tsukuba
Naho Ayuzawa: National Hospital Organization, Utano National Hospital
Hidetoshi Yanagida: National Hospital Organization, Utano National Hospital
Tetsuya Horita: Hokkaido University
Tatsuya Atsumi: Hokkaido University
Hirahito Endo: Toho University, Rheumatic Disease Center
Yoshihito Shima: Osaka University Graduate School of Medicine
Atsushi Kumanogoh: Osaka University Graduate School of Medicine
Jun Hirata: Osaka University, Statistical Immunology
Nao Otomo: The Laboratory for Statistical and Translational Genetics
Hiroyuki Suetsugu: The Laboratory for Statistical and Translational Genetics
Yoshinao Koike: The Laboratory for Statistical and Translational Genetics
Kohei Tomizuka: The Laboratory for Statistical and Translational Genetics
Soichiro Yoshino: The Laboratory for Statistical and Translational Genetics
Xiaoxi Liu: The Laboratory for Statistical and Translational Genetics
Shuji Ito: The Laboratory for Statistical and Translational Genetics
Keiko Hikino: The Laboratory for Pharmacogenomics
Akari Suzuki: The Laboratory for Autoimmune Diseases
Yukihide Momozawa: The Laboratory for Genotyping Development
Shiro Ikegawa: The Laboratory for Bone and Joint Diseases
Yoshiya Tanaka: University of Occupational and Environmental Health, Japan
Osamu Ishikawa: Gunma University Graduate School of Medicine
Kazuhiko Takehara: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
Takeshi Torii: Torii Clinic
Shinichi Sato: The University of Tokyo
Yukinori Okada: Osaka University, Statistical Immunology
Tsuneyo Mimori: Graduate School of Medicine, Kyoto University
Fumihiko Matsuda: Kyoto University, Center for Genomic Medicine
Koichi Matsuda: The University of Tokyo, Laboratory of Genome Technology, Human Genome Center
Tiffany Amariuta: Harvard Medical School
Issei Imoto: Aichi Cancer Center Research Institute
Keitaro Matsuo: Division of Cancer Epidemiology and Prevention
Masataka Kuwana: Nippon Medical School Graduate School of Medicine
Yasushi Kawaguchi: Tokyo Women’s Medical University, Division of Rheumatology, Department of Internal Medicine
Koichiro Ohmura: Graduate School of Medicine, Kyoto University
Chikashi Terao: The Laboratory for Statistical and Translational Genetics

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44541-z

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