Dissecting the mechanism of autoimmune diseases using sQTL in immune cells

• Project/Area Number: 18H02849
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kochi Yuta 東京医科歯科大学, 難治疾患研究所, 教授 (60415156)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥15,470,000 (Direct Cost: ¥11,900,000、Indirect Cost: ¥3,570,000); Fiscal Year 2020: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 自己免疫疾患 / sQTL / ゲノムワイド関連解析 / ロングリードシークエンス / long-read RNA-seq / GWAS / splicing QTL

Outline of Final Research Achievements

Genome-wide association studies have identified more than 100 candidate loci for autoimmune diseases. In this study, we identified a total of 159,369 isoforms by RNA-seq in 29 immune-cell subsets using long-read sequencing technology. Some of these were splicing QTLs (sQTLs) whose expression levels were regulated by gene variants, and were causal mechanisms for rheumatoid arthritis and systemic lupus erythematosus.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、免疫遺伝子の多くには、選択的スプライシングによって複数のアイソフォームが存在し、その発現量は遺伝子多型によって制御されていることが明らかになった。これらのアイソフォームカタログを、公共データベースに登録予定であるが、今後、様々な多因子免疫疾患の病因解析に利用可能である。

Research Products

• [Journal Article] Splicing QTL analysis focusing on coding sequences reveals pathogenicity of disease susceptibility loci (2022)
  • Author(s): Yamaguchi Kensuke、Ishigaki Kazuyoshi、Suzuki Akari、Tsuchida Yumi、Tsuchiya Haruka、Sumitomo Shuji、Nagafuchi Yasuo、Miya Fuyuki、Tsunoda Tatsuhiko、Hirofumi Shoda、Fujio Keishi、Yamamoto Kazuhiko、Kochi Yuta
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2021.12.30.474578
• [Journal Article] Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus (2022)
  • Author(s): Takeshima Yusuke、Iwasaki Yukiko、Nakano Masahiro、Narushima Yuta、Ota Mineto、Nagafuchi Yasuo、Sumitomo Shuji、Okamura Tomohisa、Elkon Keith、Ishigaki Kazuyoshi、Suzuki Akari、Kochi Yuta、Yamamoto Kazuhiko、Fujio Keishi
  • Journal Title: Annals of the Rheumatic Diseases Volume: - Issue: 6 Pages: 845-853
  • DOI: 10.1136/annrheumdis-2021-221464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases (2021)
  • Author(s): Ota M, Nagafuchi Y, Hatano H, Ishigaki K, Terao C, Takeshima Y, Yanaoka H, Kobayashi S, Okubo M, Shirai H, Sugimori Y, Maeda J, Nakano M, Yamada S, Yoshida R, Tsuchiya H, Tsuchida Y, Iwasaki Y, Sumitomo S, Shoda H, Kochi Y, Okada Y, Yamamoto K, Okamura T, Fujio K, et al.
  • Journal Title: Cell Volume: 184 Issue: 11 Pages: 1-16
  • DOI: 10.1016/j.cell.2021.03.056
  • Peer Reviewed
• [Journal Article] Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling (2019)
  • Author(s): Motegi Tomoki、Kochi Yuta、Matsuda Koichi、Kubo Michiaki、Yamamoto Kazuhiko、Momozawa Yukihide
  • Journal Title: Annals of the Rheumatic Diseases Volume: 78 Issue: 8 Pages: 1062-1069
  • DOI: 10.1136/annrheumdis-2019-215062
  • Peer Reviewed / Open Access
• [Journal Article] Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians (2019)
  • Author(s): Molineros Julio E.、Looger Loren L.、Kim Kwangwoo、Okada Yukinori、Terao Chikashi、Sun Celi、Zhou Xu-jie、Raj Prithvi、Kochi Yuta、Suzuki Akari et al.
  • Journal Title: PLOS Genetics Volume: 15 Issue: 4 Pages: 1008092-1008092
  • DOI: 10.1371/journal.pgen.1008092
  • NAID: 120006885404
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes (2019)
  • Author(s): Akizuki S, Ishigaki K, Kochi Y, Law SM, Matsuo K, Ohmura K, Suzuki A, Nakayama M, Iizuka Y, Koseki H, Ohara O, Hirata J, Kamatani Y, Matsuda F, Sumida T, Yamamoto K, Okada Y, Mimori T, Terao C.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 78 Issue: 4 Pages: 509-518
  • DOI: 10.1136/annrheumdis-2018-214116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Splicing variant ofWDFY4augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis (2018)
  • Author(s): Kochi Yuta et al.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 77 Issue: 4 Pages: 602-611
  • DOI: 10.1136/annrheumdis-2017-212149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] eQTL/sQTLから明らかにする多因子疾患の病態 (2021)
  • Author(s): 高地 雄太
  • Organizer: 日本オミクス医学会
  • Invited
• [Presentation] 自己免疫疾患のゲノム解析～ゲノム精密医療に向けて～ (2021)
  • Author(s): 高地 雄太
  • Organizer: 日本リウマチ学会
  • Invited
• [Presentation] What can we learn from eQTL studies in disease genetics? (2019)
  • Author(s): Yuta Kochi
  • Organizer: The 4th Symposium of the Inter-University Research Network for Trans-Omics Medicine
  • Int'l Joint Research
• [Presentation] 自己免疫疾患感受性多型のsplicing QTL effectを介したtrans-eQTL effectの網羅的評価 (2018)
  • Author(s): 山口 健介, 高地 雄太, 石垣 和慶, 太田 峰人, 竹島 雄介, 土田 優美, 土屋 遥香, 住友 秀次, 櫻井 恵一, 仲地 真一郎, 永渕 泰雄, 庄田 宏文, 藤尾 圭志, 山本 一彦
  • Organizer: 日本リウマチ学会