1. GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
- Author
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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
- Subjects
Science - 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.
- Published
- 2024
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