Letter | Published:

Variant between CPT1B and CHKB associated with susceptibility to narcolepsy

Nature Genetics 40, 1324–1328 (2008) | Download Citation

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Abstract

Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB1*1501 (M17378) and HLA-DQB1*0602 (M20432). Susceptibility genes other than those in the HLA region are also likely involved. We conducted a genome-wide association study using 500K SNP microarrays in 222 Japanese individuals with narcolepsy and 389 Japanese controls, with replication of top hits in 159 Japanese individuals with narcolepsy and 190 Japanese controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. rs5770917, a SNP located between CPT1B and CHKB, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 × 10−7) and other ancestry groups (OR = 1.40, P = 0.02). Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates β-oxidation, a pathway involved in regulating theta frequency during REM sleep, and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.

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Acknowledgements

We would like to express our sincere thanks to the study participants. This study was supported by Grants-in-Aid for Scientific Research on Priority Areas “Comprehensive Genomics” and “Applied Genomics” from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grant-in-Aid for JSPS fellows, and US National Institutes of Health grant NS 23724 to E. Mignot, a Howard Hughes Investigator.

Author information

Affiliations

  1. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.

    • Taku Miyagawa
    • , Minae Kawashima
    • , Nao Nishida
    • , Jun Ohashi
    • , Ryosuke Kimura
    • , Akihiro Fujimoto
    • , Mihoko Shimada
    •  & Katsushi Tokunaga

  2. Department of Sleep Disorder Research, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.

    • Minae Kawashima

  3. Department of Forensic Medicine, Tokai University School of Medicine, Ishehara 259-1100, Japan.

    • Ryosuke Kimura

  4. Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-0000, Japan.

    • Shinichi Morishita
    •  & Takashi Shigeta

  5. Center for Narcolepsy, Stanford University School of Medicine, Palo Alto, California 94305, USA.

    • Ling Lin
    • , Juliette Faraco
    •  & Emmanuel Mignot

  6. Department of Neuropsychiatry, St. Vincent's Hospital, The Catholic University of Korea, Suwon 442-723, Republic of Korea.

    • Seung-Chul Hong
    • , Yoon-Kyung Shin
    •  & Jong-Hyun Jeong

  7. Tokyo Metropolitan Matsuzawa Hospital, Tokyo 156-0057, Japan.

    • Yuji Okazaki

  8. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.

    • Shoji Tsuji

  9. The 21st Century COE Program, Center for Integrated Brain Medical Science, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.

    • Shoji Tsuji

  10. Department of Sleep Disorders Research, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan.

    • Makoto Honda

  11. Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo 151-0053, Japan.

    • Makoto Honda
    •  & Yutaka Honda

  12. Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California 94305, USA.

    • Emmanuel Mignot

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Contributions

Study design: T.M., M.K., E.M. and K.T.; sample collection: T.M., M.K., L.L., S.-C.H., J.F., Y.-K.S., J.-H.J., Y.O., S.T., M.H., Y.H. and E.M.; genotyping: T.M., M.K., N.N., M.S., L.L., J.F., E.M. and K.T.; statistical analysis: T.M., J.O., R.K., A.F., S.M., T.S., M.H., E.M. and K.T.; real-time quantitative RT-PCR: T.M. and M.H.; manuscript writing: T.M., M.K., E.M. and K.T.

Corresponding author

Correspondence to Katsushi Tokunaga.

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DOI

https://doi.org/10.1038/ng.231

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