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Genome-wide association study of idiopathic hypersomnia in a Japanese population

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Abstract

Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer’s disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations.

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Acknowledgements

The authors are deeply grateful to all participants in the present study.

Funding

This study was supported by a Practical Research Project for Rare/Intractable Diseases grant from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15H04709 and 19H03588), Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (21K07534) and Grants-in-Aid from the Takeda Science Foundation. The funders had no role in study design, data collection, analysis, the decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Kotomi Tanida, Mihoko Shimada, Seik-Soon Khor, Hiromi Toyoda, Kayoko Kato, Katsushi Tokunaga & Taku Miyagawa

  2. Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

    Mihoko Shimada, Tohru Kodama, Makoto Honda & Taku Miyagawa

  3. Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan

    Mihoko Shimada, Seik-Soon Khor & Katsushi Tokunaga

  4. Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan

    Nozomu Kotorii, Takao Kato, Hiroshi Hiejima, Motohiro Ozone & Naohisa Uchimura

  5. Kotorii Isahaya Hospital, Nagasaki, Japan

    Nozomu Kotorii & Tatayu Kotorii

  6. Ariyoshi Sleep Clinic, Fukuoka, Japan

    Yu Ariyoshi

  7. Sleep Center, Kuwamizu Hospital, Kumamoto, Japan

    Azusa Ikegami & Kazuhiko Kume

  8. Department of Stem Cell Biology, Institute of Molecular Genetics and Embryology, Kumamoto University, Kumamoto, Japan

    Kazuhiko Kume

  9. Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi, Japan

    Kazuhiko Kume

  10. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan

    Takashi Kanbayashi, Hideaki Kondo & Kazuo Mishima

  11. Ibaraki Prefectural Medical Center of Psychiatry, Ibaraki, Japan

    Takashi Kanbayashi

  12. Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan

    Aya Imanishi & Kazuo Mishima

  13. Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

    Yuichi Kamei

  14. Kamisuwa Hospital, Nagano, Japan

    Yuichi Kamei

  15. Department of Sleep-Wake Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan

    Akiko Hida & Kazuo Mishima

  16. Department of Psychiatry, Hannan Hospital, Osaka, Japan

    Yamato Wada & Kenji Kuroda

  17. Department of Neurology, Dokkyo Medical University, Tochigi, Japan

    Masayuki Miyamoto & Koichi Hirata

  18. Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan

    Masanori Takami & Naoto Yamada

  19. Department of Sleep Medicine, Shiga University of Medical Science, Shiga, Japan

    Masako Okawa

  20. Japan Foundation for Neuroscience and Mental Health, Tokyo, Japan

    Masako Okawa

  21. Department of Somnology, Tokyo Medical University, Tokyo, Japan

    Masako Okawa & Yuichi Inoue

  22. Department of Nursing, Faculty of Health Science, Fukui Health Science University, Fukui, Japan

    Naoto Omata

  23. Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

    Naoto Omata

  24. Yoyogi Sleep Disorder Center, Neuropsychiatric Research Institute, Tokyo, Japan

    Yuichi Inoue

  25. Seiwa Hospital, Neuropsychiatric Research Institute, Tokyo, Japan

    Makoto Honda

Authors
  1. Kotomi Tanida
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  2. Mihoko Shimada
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  3. Seik-Soon Khor
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  4. Hiromi Toyoda
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  31. Makoto Honda
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  32. Katsushi Tokunaga
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  33. Taku Miyagawa
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Corresponding author

Correspondence to Taku Miyagawa.

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Conflict of interest

Dr. Inoue Yuichi has received grants and payment for lectures, including service on speakers’ bureaus, and has provided expert testimony for MSD K.K., Takeda Pharmaceutical Co. Ltd., and Eisai Co. Ltd. Dr. Makoto Honda has received consulting fees from Takeda Pharmaceutical Co. Ltd. The other authors have no competing interests to declare.

Ethics approval

This research involved human participants. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All individuals provided written informed consent for participation in this study.

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Tanida, K., Shimada, M., Khor, SS. et al. Genome-wide association study of idiopathic hypersomnia in a Japanese population. Sleep Biol. Rhythms 20, 137–148 (2022). https://doi.org/10.1007/s41105-021-00349-2

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