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Phenome-wide association analysis and elucidation of the molecular basis of hypersomnia by Japanese-specific genetic variants

Research Project

Project/Area Number 21K07534
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

KODAMA Tohru  公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 研究員 (20195746)

Co-Investigator(Kenkyū-buntansha) 宮川 卓  公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 副参事研究員 (20512263)
嶋多 美穂子  国立研究開発法人国立国際医療研究センター, 研究所, ゲノム医科学プロジェクト 上級研究員 (50792727)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords睡眠 / 特発性過眠症 / オレキシン / ゲノム / 変異 / ナルコレプシー / 東北メディカルメガバンク機構 / ゲノム解析 / 眠気 / バイオバンク / 関連解析 / 遺伝要因 / 過眠症 / フェノムワイド関連解析
Outline of Research at the Start

日本人の過眠症の睡眠表現型に影響を与えている日本人特異的な変異を同定することを目的とする。これまで異質性の高い過眠症のサブタイプを変異という分子レベルで解明することは誰も達成できていないが、特定の表現型フェノタイプに着目したフェノムワイド関連解析(PheWAS)はこれを可能とすると考えた。これに成功すれば、将来的にゲノム情報に基づいて、それぞれの分子基盤を有する個人に対して、適切な診断を行うことが可能となる。

Outline of Final Research Achievements

Association analyses were performed to identify genetics variants associated with idiopathic hypersomnia (IH). We found a significant association between IH and a rare missense variant located in the cleavage site of prepro-orexin gene (p.Lys68Arg). We confirmed that the association was replicated by a different sample set (IH and healthy control). Subjective sleepiness severity was higher in the orexin mutation-positive patients. Functional analyses of this missense variant revealed that the cleavage efficiency of the mutant allele was significantly lower and the non-cleaved form had significantly lower pharmacological activity. We conducted an association analysis genotype data and self-reported sleep data in Japanese individuals from the Tohoku Medical Megabank Project cohort. No significant association was observed between p.Lys68Arg and sleep phenotypes. However, a rare variant (rs188018846) located in orexin receptor-2 gene was significantly associated with daytime sleepiness.

Academic Significance and Societal Importance of the Research Achievements

特発性過眠症はヘテロジニアスな疾患であり、その原因もほとんどわかっていない。本研究により、特発性過眠症や日中の眠気の原因の一つにオレキシンのパスウェイが関わることを明らかにした。オレキシンは睡眠覚醒制御に関わる神経ペプチドとして知られている。これまでナルコレプシーの発症にオレキシンが寄与すると考えられ、ナルコレプシー治療薬の重要なターゲットとされてきた。本研究の結果から、オレキシンが特発性過眠症の治療薬の候補ともなり得る。また、特発性過眠症や日中の眠気と関連した二つの変異は、どちらもヨーロッパ系集団やアフリカ系集団では、ほとんど認められない変異であり、集団特異的な解析の重要性も示唆された。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (14 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (2 results) Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (5 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Remarks (2 results)

  • [Int'l Joint Research] Stanford University(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Stanford University(米国)

    • Related Report
      2022 Research-status Report
  • [Journal Article] Identification of region-specific gene isoforms in the human brain using long-read transcriptome sequencing2024

    • Author(s)
      Shimada Mihoko、Omae Yosuke、Kakita Akiyoshi、Gabdulkhaev Ramil、Hitomi Yuki、Miyagawa Taku、Honda Makoto、Fujimoto Akihiro、Tokunaga Katsushi
    • Journal Title

      Science Advances

      Volume: 10 Issue: 4

    • DOI

      10.1126/sciadv.adj5279

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Narcolepsy type I-associated DNA methylation and gene expression changes in the human leukocyte antigen region2023

    • Author(s)
      Yoshida-Tanaka Kugui、Shimada Mihoko、Honda Yoshiko、Fujimoto Akihiro、Tokunaga Katsushi、Honda Makoto、Miyagawa Taku
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 10464-10464

    • DOI

      10.1038/s41598-023-37511-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia2022

    • Author(s)
      Miyagawa Taku、Tanaka Susumu、Shimada Mihoko、Sakai Noriaki、Kanbayashi Takashi、Imanishi Aya、Nishino Seiji、Mishima Kazuo、Tokunaga Katsushi、Honda Makoto
    • Journal Title

      npj Genomic Medicine

      Volume: 7 Issue: 1 Pages: 29-29

    • DOI

      10.1038/s41525-022-00298-w

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A variant in orexin receptor-2 is associated with self-reported daytime sleepiness in the Japanese population2022

    • Author(s)
      Miyagawa Taku、Shimada Mihoko、Honda Yoshiko、Kodama Tohru、Tokunaga Katsushi、Honda Makoto
    • Journal Title

      Journal of Human Genetics

      Volume: ー Issue: 6 Pages: 377-380

    • DOI

      10.1038/s10038-022-01015-2

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Genome-wide association study of idiopathic hypersomnia in a Japanese population2021

    • Author(s)
      Tanida Kotomi、Shimada Mihoko、Khor Seik-Soon、Toyoda Hiromi、Kato Kayoko、Kotorii Nozomu、Kotorii Tatayu、Ariyoshi Yu、Kato Takao、Hiejima Hiroshi、Ozone Motohiro、Uchimura Naohisa、他15名、Kodama Tohru、Inoue Yuichi、Mishima Kazuo、Honda Makoto、Tokunaga Katsushi、Miyagawa Taku
    • Journal Title

      Sleep and Biological Rhythms

      Volume: 20 Issue: 1 Pages: 137-148

    • DOI

      10.1007/s41105-021-00349-2

    • NAID

      40022811037

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] A Genetic Variant in prepro-orexin is Associated with Idiopathic Hypersomnia.2023

    • Author(s)
      Miyagawa T, Shimada M, Honda M.
    • Organizer
      3rd Asian Narcolepsy & Hypersomnolence Society Meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] オレキシン前駆体遺伝子の稀な変異と特発性過眠症との関連2023

    • Author(s)
      宮川卓、田中進、嶋多美穂子、三島和夫、徳永勝士、本多真
    • Organizer
      第46回 日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] オレキシン前駆体遺伝子の稀な変異と特発性過眠症との関連2022

    • Author(s)
      宮川 卓 他
    • Organizer
      日本人類遺伝学会第67回大会
    • Related Report
      2022 Research-status Report
  • [Presentation] 特発性過眠症感受性遺伝子の同定2022

    • Author(s)
      宮川 卓
    • Organizer
      日本睡眠学会第47回定期学術集会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia2022

    • Author(s)
      宮川 卓 他
    • Organizer
      アメリカ人類遺伝学会(ASHG)2022
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Remarks] 公益財団法人東京都医学総合研究所 睡眠プロジェクト

    • URL

      https://www.igakuken.or.jp/sleep/

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
  • [Remarks] 公益財団法人東京都医学総合研究所 精神行動医学研究分野 睡眠プロジェクト

    • URL

      https://www.igakuken.or.jp/sleep/

    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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