GWAS for Systemic Sclerosis Identified six novel susceptibility loci including penetrating Fcγ-Receptor Region

Author:

Ishikawa Yuki1ORCID,Tanaka Nao2ORCID,Asano Yoshihide3,Kodera Masanari4,Shirai Yuichiro5,Akahoshi Mitsuteru6,Hasegawa Minoru7,Matsushita Takashi8ORCID,Saito Kazuyoshi9,Motegi Sei-ishiro10,Yoshifuji Hajime11,Yoshizaki Ayumi12,Komoto Tomohiro13,Takagi Kae14,Oka Akira15,Kanda Miho4,Tanak Yoshihito4,Ito Yumi4,Nakano Kazuhisa16,Kasamatsu Hiroshi17,Utsunomiya Akira17,Sekiguchi Akiko10,Niro Hiroaki6,Jinnin Masatoshi18,Makino Katsunari19,Makino Takamitsu19,Ihn Hironobu19,Yamamoto Motohisa20,Suzuki Chisako21,Takahashi Hiroki21,Nishida Emi22,Morita Akimichi23ORCID,Yamamoto Toshiyuki24ORCID,Fujimoto Manabu25ORCID,Kondo Yuya26,Goto Daisuke27,Sumida Takayuki26,Ayuzawa Naho28,Yanagida Hidetashi28,Horita Tetsuya,Atsumi Tatsuya29ORCID,Endo Hirahito30,Shima Yoshihito31ORCID,Kumanogoh Atsushi25ORCID,Hirata Jun25,Otomo Nao2,Suetsugu Hiroyuki2,Koike Yoshinao32ORCID,Tomizuka Kohei32,Yoshino Soichiro32,Liu Xiaoxi2,Ito Shuji2,Hikino Keiko32ORCID,Suzuki Akari33,Momozawa Yukihide32ORCID,Ikegawa Shiro2,Tanaka Yoshiya34ORCID,Ishikawa Osamu10,Takehara Kazuhiko8,Torii Takeshi35,Sato Shinichi36,Okada Yukinori31ORCID,Mimori Tsuneyo37,Matsuda Fumihiko11,Matsuda Koichi3ORCID,Amariuta Tiffany38,Imoto Issei13,Matsuo Keitaro13ORCID,Kuwana Masataka39,Kawaguchi Yasushi14,Ohmura Koichiro37,Terao Chikashi2ORCID

Affiliation:

1. RIKEN, Center for Integrative Medical Sciences

2. RIKEN Center for Integrative Medical Sciences

3. University of Tokyo

4. Chukyo Hospital, Japan Community Health Care Organization

5. Nippon Medical School Graduate School of Medicine

6. Kyushu University, Faculty of Medicine

7. University of Fukui

8. Kanazawa University

9. University of Occupational and Environmental Health, Japan

10. Gunma University Graduate School of Medicine

11. Kyoto University Graduate School of Medicine

12. The University of Tokyo

13. Aichi Cancer Center Research Institute

14. Tokyo Women's Medical University

15. Tokai University

16. School of Medicine, University of Occupational and Environmental Health

17. Faculty of Medical Sciences, University of Fukui

18. Wakayama Medical University Graduate School of Medicine

19. Kumamoto University

20. Sapporo Medical University

21. Sapporo Medical University School of Medicine

22. Nagoya City University Graduate School of Medical Sciences

23. Nagoya City University

24. Fukushima Medical University

25. Osaka University

26. University of Tsukuba

27. Faculty of Medicine, University of Tsukuba

28. National Hospital Organization, Utano National Hospital,

29. Hokkaido University Graduate School of Medicine

30. Toho University

31. Osaka University Graduate School of Medicine

32. RIKEN

33. Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

34. University of Occupational and Environmental Health Japan

35. Torii Clinic

36. University of Tokyo Graduate School of Medicine

37. Graduate School of Medicine, Kyoto University

38. UCSD

39. Nippon Medical School, Department of Allergy and Rheumatology, 1-1-5 Sendagi, Bunkyo-ku

Abstract

Abstract We conducted a Japanese GWAS for systemic sclerosis (SSc) comprising 1,428 cases and 112,599 controls, the largest Asian GWAS for SSc ever, and identified three novel signals. The lead SNP in FCGR/FCRL region had a strong effect size (OR 2.05, P = 4.9×10−11). The complete LD SNP, rs10917688, was found in a cis-regulatory element and a part of binding motifs for IRF8. IRF8 was a significant locus in the European GWAS and rs10917688 showed an association only in the presence of the risk allele of IRF8 in Japanese. rs10917688 was marked with H3K4me1 in primary B cells, and the heritability was enriched in active histone marks of primary B cells. A meta-analysis with the latest European GWAS found additional 30 significant loci including three novel signals. PRS constructed with the effect sizes of the meta-analysis indicated potential portability of genetic associations beyond populations (AUC: 0.593). The fitting of PRS was improved by further prioritizing the top 5% SNPs of IRF8 biding sites in B cells, underscoring common genetic architecture across populations and critical roles of B cells and IRF8 for SSc development.

Publisher

Research Square Platform LLC

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