Genetic factors and molecular mechanisms in the development of circadian rhythm sleep-wake disorders

• Project/Area Number: 18K07580
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Hida Akiko 国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 睡眠・覚醒障害研究部, 客員研究員 (20333354)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 睡眠障害 / 概日リズム / 遺伝子 / 概日リズム睡眠－覚醒障害 / 非24時間睡眠－覚醒リズム障害 / 概日時計 / 遺伝子バリアント / 睡眠 / 次世代シーケンス / 時計遺伝子 / 遺伝マーカー / 生物時計

Outline of Final Research Achievements

To identify potential genetic factors contributing to the development of non-24-hour sleep-wake disorder (N24SWD), a subtype of circadian rhythm sleep-wake disorder, targeted sequencing of 76 genes was performed using next-generation sequencing in 17 sighted Japanese individuals with N24SWD. Sanger sequencing of the CLOCK and NR1D2 coding regions was then performed in a total of 64 sighted Japanese individuals with N24SWD, including the 17 N24SWD individuals. One novel and four known CLOCK variants and one novel and eight known NR1D2 variants were identified in our study population of 64 N24SWD individuals. In addition, the novel PER1 variant was found in the N24SWD individual carrying the novel NR1D2 variant.

Academic Significance and Societal Importance of the Research Achievements

概日リズム睡眠－覚醒障害は、定まった時刻に寝起きすることができず、通常の社会生活へ適応することが困難となる睡眠障害である。概日リズム睡眠－覚醒障害の発症には内因性の生物時計周期の延長や光同調機能不全が関わっているとされているが、その分子機序は未だ明らかにされていない。本研究では、概日リズム睡眠－覚醒障害のサブタイプである非24時間睡眠－覚醒リズム障害に関わる潜在的な遺伝的要因が特定され、概日リズム睡眠－覚醒障害発症機序の解明、ヒトにおける概日リズムと睡眠調節分子機序の解明に貢献することが期待される。

Research Products

• [Journal Article] Novel CLOCK and NR1D2 variants in 64 sighted Japanese individuals with non-24-hour sleep-wake rhythm disorder (2023)
  • Author(s): Hida A, Iida A, Ukai M, Kadotani H, Uchiyama M, Ebisawa T, Inoue Y, Kitamura S, Mishima K.
  • Journal Title: Sleep Volume: － Issue: 6 Pages: 1-3
  • DOI: 10.1093/sleep/zsad063
  • Peer Reviewed / Open Access
• [Journal Article] Lack of association between PER3 variable number tandem repeat and circadian rhythm sleep-wake disorders (2018)
  • Author(s): Hida A, Kitamura S, Kadotani H, Uchiyama M, Ebisawa T, Inoue Y, Kamei Y, Mishima K
  • Journal Title: Human Genome Variation Volume: 5 Issue: 1 Pages: 17-17
  • DOI: 10.1038/s41439-018-0017-7
  • NAID: 120006539730
  • Peer Reviewed / Open Access
• [Journal Article] A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia (2018)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Kanbayashi T, Imanishi A, Sagawa Y, Kotorii N, Kotorii T, Ariyoshi Y, Hashizume Y, Ogi K, Hiejima H, Kamei Y, Hida A, et al.
  • Journal Title: J Hum Genet Volume: 63 Issue: 12 Pages: 1259-1267
  • DOI: 10.1038/s10038-018-0518-8
  • Peer Reviewed / Open Access
• [Journal Article] 概日リズムを末梢で計測する (2018)
  • Author(s): 肥田昌子
  • Journal Title: CLINICAL NEUROSCIENCE Volume: 36 Pages: 1107-1108
• [Presentation] 家族性概日リズム睡眠-覚醒相前進障害の新規遺伝要因 (2019)
  • Author(s): 鵜飼基生、肥田昌子、北村真吾、井上雄一、三島和夫
  • Organizer: 第26回日本時間生物学会学術大会
• [Presentation] 76遺伝子を対象とした非24時間睡眠-覚醒リズム障害遺伝要因の探索 (2018)
  • Author(s): 肥田昌子、鵜飼基生、北村真吾、綾部直子、加藤美恵、亀井雄一、三島和夫
  • Organizer: 日本睡眠学会第43回定期学術集会
• [Presentation] 家族性概日リズム睡眠-覚醒相前進障害に関わる遺伝要因の探索 (2018)
  • Author(s): 鵜飼基生、肥田昌子、北村真吾、加藤美恵、井上雄一、三島和夫
  • Organizer: 日本睡眠学会第43回定期学術集会