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Establishment of a novel strategy for pathological analysis of multifactorial diseases using genetic risk variants

Research Project

Project/Area Number 18H05285
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Review Section Broad Section I
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

Yamamoto Kazuhiko  国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (80191394)

Co-Investigator(Kenkyū-buntansha) 鈴木 亜香里  国立研究開発法人理化学研究所, 生命医科学研究センター, 副チームリーダー (00391996)
庄田 宏文  東京大学, 医学部附属病院, 准教授 (20529036)
尾崎 浩一  国立研究開発法人国立長寿医療研究センター, 研究所 メディカルゲノムセンター, センター長 (50373288)
寺尾 知可史  国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (60610459)
Project Period (FY) 2018-06-11 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥193,440,000 (Direct Cost: ¥148,800,000、Indirect Cost: ¥44,640,000)
Fiscal Year 2022: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2021: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2020: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2019: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2018: ¥41,600,000 (Direct Cost: ¥32,000,000、Indirect Cost: ¥9,600,000)
Keywords多因子疾患 / 免疫疾患 / ヒト免疫 / ゲノムワイド関連解析 / 疾患感受性遺伝子変異 / 量的形質遺伝子座 / QTL解析 / 免疫細胞分画 / 疾患関連遺伝子多型 / 遺伝子発現量解析 / プロモーターエンハンサー解析 / ゲノム / エピゲノム / 遺伝子発現量 / プロモーター / エンハンサー / オープンクロマチン解析 / シングルセル解析 / 遺伝子多型 / マルチオミクス解析 / eQTL解析 / クロマチン構造解析 / クロマチンステイタス解析 / 多因子性疾患 / 一塩基多型 / ホールトランスクリプトーム解析 / オミックス / エピゲノム解析
Outline of Final Research Achievements

To analyze the pathogenesis of human multifactorial diseases, we aimed to establish a methodology to identify causally related intermediate phenotypes based on the principle that genomic factors are causally related to diseases. In this study, we focused on the immune system, and aimed to identify causal factors related to genomic factors among intermediate phenotypes such as gene expression and epigenomic alterations in each immune cell, and to construct a cell-specific catalog of such factors. The construction of the catalog has been almost completed, and it is now ready for application to immune system analysis.

Academic Significance and Societal Importance of the Research Achievements

ゲノムワイド関連解析の方法が確立され、多くの多因子疾患でリスク遺伝子変異が明らかにされているが、疾患の理解や創薬に十分に結びついていない。本研究はそれを解決する方法論を示している。具体的には、社会的要請が高いワクチン開発に関して、令和4年度にAMEDのワクチン開発のための「ヒト免疫サポート機関」に選定され、現在、我々が構築したシステムをより発展させ、少量のサンプルからそれぞれの個人の免疫応答機能を予測するシステムの構築を進めている。

Assessment Rating
Ex-post Assessment Comments (Rating)

B: In light of the aim of introducing the research area into the research categories, research outcomes have been produced to a certain extent, but not sufficient.

Assessment Rating
Interim Assessment Comments (Rating)

A-: In light of the aim of introducing the research area into the research categories, the expected progress in research has been made on the whole though a part of it has been delayed.

Report

(11 results)
  • 2023 Ex-post Assessment (Comments) ( PDF )
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Abstract (Interim Assessment) ( PDF )   Annual Research Report   Interim Assessment (Comments) ( PDF )
  • 2019 Annual Research Report
  • 2018 Abstract ( PDF )   Comments on the Screening Results ( PDF )   Annual Research Report
  • Research Products

    (32 results)

All 2022 2021 2020 2019 2018 Other

All Journal Article (20 results) (of which Int'l Joint Research: 11 results,  Peer Reviewed: 17 results,  Open Access: 17 results) Presentation (11 results) (of which Int'l Joint Research: 10 results,  Invited: 11 results) Remarks (1 results)

  • [Journal Article] Immune cell multiomics analysis reveals contribution of oxidative phosphorylation to B-cell functions and organ damage of lupus2022

    • 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

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct transcriptome architectures underlying lupus establishment and exacerbation2022

    • Author(s)
      Nakano Masahiro et al.
    • Journal Title

      Cell

      Volume: 185 Issue: 18 Pages: 3375-3389.e21

    • DOI

      10.1016/j.cell.2022.07.021

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci2022

    • Author(s)
      Yamaguchi Kensuke、Ishigaki Kazuyoshi、Suzuki Akari、Tsuchida Yumi、Tsuchiya Haruka、Sumitomo Shuji、Nagafuchi Yasuo、Miya Fuyuki、Tsunoda Tatsuhiko、Shoda Hirofumi、Fujio Keishi、Yamamoto Kazuhiko、Kochi Yuta
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 4659-4659

    • DOI

      10.1038/s41467-022-32358-1

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional genomics of autoimmune diseases2021

    • Author(s)
      Suzuki Akari、Guerrini Matteo Maurizio、Yamamoto Kazuhiko
    • Journal Title

      Annals of the Rheumatic Diseases

      Volume: 無 Issue: 6 Pages: 689-697

    • DOI

      10.1136/annrheumdis-2019-216794

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis2020

    • Author(s)
      Tsuchiya Haruka、Ota Mineto、Sumitomo Shuji、Ishigaki Kazuyoshi、Suzuki Akari、Sakata Toyonori、Tsuchida Yumi、Inui Hiroshi、Hirose Jun、Kochi Yuta、Kadono Yuho、Shirahige Katsuhiko、Tanaka Sakae、Yamamoto Kazuhiko、Fujio Keishi
    • Journal Title

      Annals of the Rheumatic Diseases

      Volume: 80 Issue: 4 Pages: 440-450

    • DOI

      10.1136/annrheumdis-2020-218189

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chromosomal alterations among age-related haematopoietic clones in Japan2020

    • Author(s)
      Terao Chikashi、Suzuki Akari、Momozawa Yukihide、Akiyama Masato、Ishigaki Kazuyoshi、Yamamoto Kazuhiko、Matsuda Koichi、Murakami Yoshinori、McCarroll Steven A.、Kubo Michiaki、Loh Po-Ru、Kamatani Yoichiro
    • Journal Title

      Nature

      Volume: 584 Issue: 7819 Pages: 130-135

    • DOI

      10.1038/s41586-020-2426-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases2020

    • Author(s)
      Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Low SK, Okada Y, Yamaji T, et al
    • Journal Title

      Nature Genetics

      Volume: 52 Issue: 7 Pages: 669-679

    • DOI

      10.1038/s41588-020-0640-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes2019

    • 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

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Shared genetic factors and their causality in autoimmune diseases2019

    • Author(s)
      Yamamoto Kazuhiko、Okada Yukinori
    • Journal Title

      Annals of the Rheumatic Diseases

      Volume: 78 Issue: 11 Pages: 1449-1451

    • DOI

      10.1136/annrheumdis-2019-215099

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IMPACT: Genomic Annotation of Cell-State-Specific Regulatory Elements Inferred from the Epigenome of Bound Transcription Factors2019

    • Author(s)
      Amariuta Tiffany、Luo Yang、Gazal Steven、Davenport Emma E.、van de Geijn Bryce、Ishigaki Kazuyoshi、Westra Harm-Jan、Teslovich Nikola、Okada Yukinori、Yamamoto Kazuhiko、Price Alkes L.、Raychaudhuri Soumya
    • Journal Title

      The American Journal of Human Genetics

      Volume: 104 Issue: 5 Pages: 879-895

    • DOI

      10.1016/j.ajhg.2019.03.012

    • Related Report
      2019 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians2019

    • 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

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of rare coding variants in TYK2 protective for rheumatoid arthritis in the Japanese population and their effects on cytokine signalling2019

    • 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

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis.2019

    • Author(s)
      Negishi H, Endo N, Nakajima Y, Nishiyama T, Tabunoki Y, Nishio J, Koshiba R, Matsuda A, Matsuki K, Okamura T, Negishi-Koga T, Ichinohe T, Takemura S, Ishiwata H, Iemura SI, Natsume T, Abe T, Kiyonari H, Doi T, Hangai S, Yanai H, Fujio K, Yamamoto K, Taniguchi T.
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 116 Issue: 47 Pages: 23653-23661

    • DOI

      10.1073/pnas.1915326116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Linking of genetic risk variants to disease-specific gene expression via multi-omics studies in rheumatoid arthritis2019

    • Author(s)
      Suzuki Akari、Terao Chikashi、Yamamoto Kazuhiko
    • Journal Title

      Seminars in Arthritis and Rheumatism

      Volume: 49 Issue: 3 Pages: S49-S53

    • DOI

      10.1016/j.semarthrit.2019.09.007

    • Related Report
      2019 Annual Research Report
    • Open Access
  • [Journal Article] Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway2019

    • Author(s)
      Ebana Yusuke、Sun Yihan、Yang Xiaoxi、Watanabe Taiju、Makita Satoru、Ozaki Kouichi、Tanaka Toshihiro、Arai Hirokuni、Furukawa Tetsushi
    • Journal Title

      IJC Heart & Vasculature

      Volume: 24 Pages: 100383-100383

    • DOI

      10.1016/j.ijcha.2019.100383

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer’s disease2019

    • Author(s)
      Asanomi Yuya、Shigemizu Daichi、Miyashita Akinori、Mitsumori Risa、Mori Taiki、Hara Norikazu、Ito Kaoru、Niida Shumpei、Ikeuchi Takeshi、Ozaki Kouichi
    • Journal Title

      Molecular Medicine

      Volume: 25 Issue: 1

    • DOI

      10.1186/s10020-019-0090-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Risk prediction models for dementia constructed by supervised principal component analysis using miRNA expression data2019

    • Author(s)
      Shigemizu D, Akiyama S, Asanomi Y, Boroevich KA, Sharma A, Tsunoda T, Matsukuma K, Ichikawa M, Sudo H, Takizawa S, Sakurai T, Ozaki K, Ochiya T, Niida S.
    • Journal Title

      Communication Biology

      Volume: 2 Issue: 1 Pages: 77-77

    • DOI

      10.1038/s42003-019-0324-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reduction of CD83 Expression on B Cells and the Genetic Basis for Rheumatoid Arthritis: Comment on the Article by Thalayasingam et al2018

    • Author(s)
      Tsuchida Yumi、Sumitomo Shuji、Ota Mineto、Tsuchiya Haruka、Nagafuchi Yasuo、Shoda Hirofumi、Fujio Keishi、Ishigaki Kazuyoshi、Yamaguchi Kensuke、Suzuki Akari、Kochi Yuta、Yamamoto Kazuhiko
    • Journal Title

      Arthritis & Rheumatology

      Volume: 70 Issue: 10 Pages: 1695-1696

    • DOI

      10.1002/art.40652

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetics of rheumatoid arthritis: 2018 status2018

    • Author(s)
      Okada Yukinori、Eyre Stephen、Suzuki Akari、Kochi Yuta、Yamamoto Kazuhiko
    • Journal Title

      Annals of the Rheumatic Diseases

      Volume: 78 Issue: 4 Pages: 446-453

    • DOI

      10.1136/annrheumdis-2018-213678

    • Related Report
      2018 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] A gene module associated with dysregulated TCR signaling pathways in CD4 + T cell subsets in rheumatoid arthritis2018

    • Author(s)
      Sumitomo Shuji、Nagafuchi Yasuo、Tsuchida Yumi、Tsuchiya Haruka、Ota Mineto、Ishigaki Kazuyoshi、Nakachi Shinichiro、Kato Rika、Sakurai Keiichi、Hanata Norio、Tateishi Shoko、Kanda Hiroko、Suzuki Akari、Kochi Yuta、Fujio Keishi、Yamamoto Kazuhiko
    • Journal Title

      Journal of Autoimmunity

      Volume: 89 Pages: 21-29

    • DOI

      10.1016/j.jaut.2017.11.001

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis2022

    • Author(s)
      Yamamoto K. Ishigaki K.
    • Organizer
      International Forum of Rheumatoid Arthritis 2022 (Beijing, China , on line), September
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Evaluation of human immune function for vaccine development2022

    • Author(s)
      Yamamoto K.
    • Organizer
      McGill-RIKEN Symposium (Montreal, Canada ) September
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Human immune diversity for infection and vaccine development2022

    • Author(s)
      Yamamoto K.
    • Organizer
      RIKEN-KI-SciLifeLab Symposium (Stockholm, Sweden) October
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Data-driven functional analysis of human lymphocytes2022

    • Author(s)
      Yamamoto K.
    • Organizer
      Tsinghua RIKEN Joint workshop (on line) November
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Immunogenetics of rheumatoid arthritis & way forward2022

    • Author(s)
      Yamamoto K.
    • Organizer
      24th Asia-Pacific League of Associations for Rheumatology (Hong Kong, China), December
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamic Landscape of immune cell-specific gene regulation.2021

    • Author(s)
      山本一彦
    • Organizer
      The 13th International Forum on Rheumatoid Arthritis (IFRA2021)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 統合オミックス解析による関節リウマチ関連遺伝子の同定2019

    • Author(s)
      鈴木亜香里、高地雄太、石垣和慶、山本一彦
    • Organizer
      第34回日本整形外科学会基礎学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Integration of Genetic information to immune functions2019

    • Author(s)
      Kazuhiko Yamamoto
    • Organizer
      Advanced Target Therapies. 27-31 March 2019 Palma, Spain
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Mapping genes to immune cells2019

    • Author(s)
      Kazuhiko Yamamoto
    • Organizer
      EULAR (European League Against Rheumatism) 12-15, June 2019 Madrid, Spain
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Integration of genetic information to immune functions2019

    • Author(s)
      Kazuhiko Yamamoto
    • Organizer
      11th International Forum on Rheumatoid Arthritis. September 25-27, September 2019, Washington DC, USA
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Genetics of Human Immune System2018

    • Author(s)
      Kazuhiko Yamamoto
    • Organizer
      McGill RIKEN symposium, 12-13rd
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 自己免疫疾患研究チーム

    • URL

      https://www.riken.jp/research/labs/ims/autoimmun_dis/index.html

    • Related Report
      2020 Annual Research Report

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Published: 2018-06-12   Modified: 2024-03-28  

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