GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
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Published:2024-01-31
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Ishikawa YukiORCID, Tanaka NaoORCID, Asano Yoshihide, Kodera Masanari, Shirai Yuichiro, Akahoshi MitsuteruORCID, Hasegawa Minoru, Matsushita TakashiORCID, Saito Kazuyoshi, Motegi Sei-ichiro, Yoshifuji Hajime, Yoshizaki Ayumi, Kohmoto Tomohiro, Takagi Kae, Oka AkiraORCID, Kanda Miho, Tanaka Yoshihito, Ito Yumi, Nakano Kazuhisa, Kasamatsu Hiroshi, Utsunomiya Akira, Sekiguchi Akiko, Niiro Hiroaki, Jinnin Masatoshi, Makino Katsunari, Makino Takamitsu, Ihn Hironobu, Yamamoto MotohisaORCID, Suzuki Chisako, Takahashi Hiroki, Nishida Emi, Morita AkimichiORCID, Yamamoto ToshiyukiORCID, Fujimoto ManabuORCID, Kondo YuyaORCID, Goto Daisuke, Sumida Takayuki, Ayuzawa Naho, Yanagida Hidetoshi, Horita TetsuyaORCID, Atsumi TatsuyaORCID, Endo Hirahito, Shima YoshihitoORCID, Kumanogoh AtsushiORCID, Hirata Jun, Otomo Nao, Suetsugu Hiroyuki, Koike YoshinaoORCID, Tomizuka Kohei, Yoshino Soichiro, Liu Xiaoxi, Ito Shuji, Hikino KeikoORCID, Suzuki Akari, Momozawa YukihideORCID, Ikegawa Shiro, Tanaka YoshiyaORCID, Ishikawa Osamu, Takehara Kazuhiko, Torii Takeshi, Sato Shinichi, Okada YukinoriORCID, Mimori Tsuneyo, Matsuda Fumihiko, Matsuda KoichiORCID, Amariuta Tiffany, Imoto Issei, Matsuo KeitaroORCID, Kuwana Masataka, Kawaguchi Yasushi, Ohmura Koichiro, Terao ChikashiORCID
Abstract
AbstractHere 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.
Funder
Japan Agency for Medical Research and Development MEXT | Japan Society for the Promotion of Science THE KATO MEMORIAL TRUST FOR NAMBYO RESEARCH Medical Research Support Project of the Shizuoka Prefectural Hospital Organization
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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