Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

A variant in orexin receptor-2 is associated with self-reported daytime sleepiness in the Japanese population

Journal of Human Genetics volume 67, pages 377–380 (2022)Cite this article

Subjects

Abstract

Excessive daytime sleepiness is characterized by a persistent feeling of having trouble staying awake, typically with inappropriate sleep episodes. Orexin (hypocretin) is a neuropeptide that regulates sleep-wake cycles and rapid eye movement sleep. Several large-scale genome-wide association studies (GWASs) in European populations have found genetic variants in orexin receptor-1 (OX1R) and -2 (OX2R) that are associated with sleep traits including daytime sleepiness. To identify genetic variants associated with daytime sleepiness, we performed an association study of genetic variants in prepro-orexin, OX1R, and OX2R in 14,329 Japanese individuals from the Tohoku Medical Megabank Project cohort. A genetic variant in OX2R was significantly associated with self-reported daytime sleepiness after Bonferroni correction (rs188018846: P = 8.4E−05). In addition, a missense variant in OX2R identified by the European GWASs showed a nominally significant association with daytime sleepiness in a Japanese population (p.Ile308Val, rs2653349: P = 0.044). Multiple genetic variants in OX2R can affect daytime sleepiness in general populations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Desai AV, Cherkas LF, Spector TD, Williams AJ. Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study. Twin Res. 2004;7:589–95.

    Article  Google Scholar 

  2. Lane JM, Liang J, Vlasac I, Anderson SG, Bechtold DA, Bowden J, et al. Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nat Genet. 2017;49:274–81.

    Article  CAS  Google Scholar 

  3. Wang H, Lane JM, Jones SE, Dashti HS, Ollila HM, Wood AR, et al. Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes. Nat Commun. 2019;10:3503.

    Article  Google Scholar 

  4. Watson NF, Goldberg J, Arguelles L, Buchwald D. Genetic and environmental influences on insomnia, daytime sleepiness, and obesity in twins. Sleep. 2006;29:645–9.

    Article  Google Scholar 

  5. Dashti HS, Daghlas I, Lane JM, Huang Y, Udler MS, Wang H, et al. Genetic determinants of daytime napping and effects on cardiometabolic health. Nat Commun. 2021;12:900.

    Article  CAS  Google Scholar 

  6. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci. 2007;8:171–81.

    Article  CAS  Google Scholar 

  7. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98:365–76.

    Article  CAS  Google Scholar 

  8. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98:437–51.

    Article  CAS  Google Scholar 

  9. Tadaka S, Katsuoka F, Ueki M, Kojima K, Makino S, Saito S, et al. 3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. Hum Genome Var. 2019;6:28.

    Article  Google Scholar 

  10. Kawai Y, Mimori T, Kojima K, Nariai N, Danjoh I, Saito R, et al. Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals. J Hum Genet. 2015;60:581–7.

    Article  CAS  Google Scholar 

  11. Kuriyama S, Yaegashi N, Nagami F, Arai T, Kawaguchi Y, Osumi N, et al. The Tohoku medical megabank project: design and mission. J Epidemiol. 2016;26:493–511.

    Article  Google Scholar 

  12. Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, et al. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat Commun. 2015;6:8018.

    Article  CAS  Google Scholar 

  13. Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5:e1000529.

    Article  Google Scholar 

  14. Gervais O, Ueno K, Kawai Y, Hitomi Y, Misawa K, Teraguchi S, et al. Genomic heritabilities and correlations of 17 traits related to obesity and associated conditions in the Japanese population. G3. 2020;10:2221–8.

    Article  CAS  Google Scholar 

  15. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    Article  CAS  Google Scholar 

  16. ICSD-3. International classification of sleep disorders. 3rd edn. Darien, IL: American Academy of Sleep Medicine; 2014.

  17. Ohashi M, Kohno T, Kohsaka S, Fukuoka R, Hayashida K, Yuasa S, et al. Excessive daytime sleepiness is associated with depression scores, but not with sleep-disordered breathing in patients with cardiovascular diseases. Circ J. 2018;82:2175–83.

    Article  CAS  Google Scholar 

  18. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    Article  CAS  Google Scholar 

  19. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22:1790–7.

    Article  CAS  Google Scholar 

  20. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–934.

    Article  CAS  Google Scholar 

  21. Tanida K, Shimada M, Khor SS, Toyoda H, Kato K, Kotorii N, et al. Genome-wide association study of idiopathic hypersomnia in a Japanese population. Sleep Biological Rhythms. 2021. https://doi.org/10.1007/s41105-021-00349-2.

  22. Toyoda H, Miyagawa T, Koike A, Kanbayashi T, Imanishi A, Sagawa Y, et al. A polymorphism in CCR1/CCR3 is associated with narcolepsy. Brain Behav Immun. 2015;49:148–55.

    Article  CAS  Google Scholar 

  23. Alkan C, Coe BP, Eichler EE. Genome structural variation discovery and genotyping. Nat Rev Genet. 2011;12:363–76.

    Article  CAS  Google Scholar 

  24. English AC, Salerno WJ, Reid JG. PBHoney: identifying genomic variants via long-read discordance and interrupted mapping. BMC Bioinforma. 2014;15:180.

    Article  Google Scholar 

  25. Benjafield AV, Ayas NT, Eastwood PR, Heinzer R, Ip MSM, Morrell MJ, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;7:687–98.

    Article  Google Scholar 

Download references

Acknowledgements

This research was conducted using the ToMMo biobank resource under research number 2019-0110. The authors are deeply grateful to all participants in the present study. This study was supported by Grants-in-Aid for Scientific Research (B) (19H03588) and (C) (21K07534) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The funder had no role in study design, data collection, analysis, the decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Taku Miyagawa, Mihoko Shimada, Yoshiko Honda, Tohru Kodama & Makoto Honda

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

    Taku Miyagawa, Mihoko Shimada & Katsushi Tokunaga

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

    Mihoko Shimada & Katsushi Tokunaga

  4. Koishikawa Tokyo Hospital, Institute of Neuropsychiatry, Tokyo, Japan

    Makoto Honda

Authors
  1. Taku Miyagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mihoko Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshiko Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tohru Kodama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katsushi Tokunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Makoto Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Taku Miyagawa.

Ethics declarations

Competing interests

MH has received consulting fees from Takeda Pharmaceutical Co. Ltd. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyagawa, T., Shimada, M., Honda, Y. et al. A variant in orexin receptor-2 is associated with self-reported daytime sleepiness in the Japanese population. J Hum Genet 67, 377–380 (2022). https://doi.org/10.1038/s10038-022-01015-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-022-01015-2

Search

Advanced search

Quick links